3-ethyl-, 3-propyl- or 3-butyl-chroman and thiochroman derivatives

ABSTRACT

A compound having the following general formula (1):                    
     in which 
     R 1  represents an ethyl group, etc.; 
     R 2  represents a hydrogen atom, etc.; 
     R 3  represents a C 1 -C 5  perhalogenoalkyl group, etc.; 
     each of R 4  and R 5  independently represents a hydrogen atom, etc.; 
     X represents an oxygen atom or a sulfur atom; 
     m represents an integer of 2 to 14; and 
     n represents an integer of 2 to 7; 
     or an enantiomer of the compound, or a hydrate or a pharmaceutically acceptable salt of the compound or its enantiomer is advantageous in pharmaceutical use because of its anti-estrogenic activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/JP00/08809, filed Dec. 13, 2000, whichclaims priority from Japanses application 11-353592, filed Dec. 13,1999.

TECHNICAL FIELD

The present invention relates to chroman or thiochroman derivativeshaving anti-estrogenic activity.

BACKGROUND ART

In treating diseases caused by abnormal tissue growth that is dependentupon a certain sexual steroidal hormone such as estrogen, it is highlyimportant to significantly inhibit, more preferably completelyeliminate, the effect induced by the hormone. For this purpose, it isdesirable to reduce the level of hormone capable of acting on thesteroidal hormone receptor site. For instance, anti-estrogenic agentsare commonly administered for alternative or combination therapy tolimit the production of estrogen to the amount less than required toactivate the receptor site. However, such conventional technique forblocking estrogen production could not sufficiently inhibit the effectinduced through the estrogen receptor. Practically, even when estrogenis completely absent, some of the receptors may be activated. It wastherefore considered that estrogen antagonists could provide bettertherapeutic effect in comparison to the technique for blocking only theproduction of sexual steroidal hormone. Thus, numerous estrogenantagonists have been developed. For example, many patent publicationsincluding U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 andWO 96/22092 disclose various anti-estrogenic compounds. Sometimes,however, prior art antagonists may themselves act as agonists, andtherefore activate rather than block the receptor. For example,Tamoxifen has been most widely used as an anti-estrogenic agent.However, this agent has a disadvantage that it exhibits estrogenicactivity in some organs (see, M. Harper and A. Walpole, J. Reprod.Fertile., 1967, 13, 101).

As another non-steroidal anti-estrogenic compound, WO 93/10741 disclosesa benzopyran derivative having an aminoethoxyphenyl substituent(s)(Endorecherche), the typical compound of which is EM-343 having thefollowing structure:

Said compound also has the agonistic effect. It is therefore required todevelop an anti-estrogenic compound which is substantially or completelyfree of agonistic effect and which can effectively block the estrogenreceptor.

In addition, it has been known that 7α-substituted derivatives ofestradiol, for example, 7α-(CH₂)₁₀CONMeBu derivatives, are steroidalanti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S.Pat. No. 4,659,516). Further, an estradiol derivative having a7α-(CH₂)₉SOC₅H₆F₅ substituent has also been disclosed (see, Wakeling etal., Cancer Res., 1991, 51, 3867).

Non-steroidal anti-estrogenic agents without agonistic effect have beenfirst reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler,J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661discloses phenol derivatives having anti-estrogenic activity. Thesephenol derivatives generally have a naphthalene scaffold and include,typically, the following compounds:

Some chroman and thiochroman derivatives have been reported asanti-estrogenic compounds having no agonistic effect (WO 98/25916).Although the existing anti-estrogenic compounds having no agonisticeffect show a substantial therapeutic effect when administered viaintravenous or subcutaneous injection, they show a highly reducedtherapeutic effect when administered orally, probably due to their lowbioavailability by oral route, etc. Therefore, for convenience's sake inthe case of administration, it is desired to develop anti-estrogeniccompounds which show a sufficient effect when administered orally and atthe same time have no agonistic effect.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide chroman or thiochromanderivatives which have anti-estrogenic activity and are advantageous inpharmaceutical use.

The present inventors have researched anti-estrogenic activity ofcompounds having various structures. As a result, we have found thatchroman and thiochroman derivatives of general formula (1) could show agood anti-estrogenic activity in substantial absence of agonistic effectand that they provided a sufficiently high activity even whenadministered orally. The present invention has been accomplished on thebasis of this finding.

Namely, the present invention provides a compound having the followinggeneral formula (1):

in which

R₁ represents an ethyl group, a n-propyl group, an i-propyl group or abutyl group;

R₂ represents a hydrogen atom or a salt-forming metal;

R₃ represents a linear or branched C₁-C₇ halogenoalkyl group;

each of R₄ and R₅ independently represents a hydrogen atom, anoptionally substituted linear or branched C₁-C₃ alkyl group, an acylgroup or a salt-forming metal;

X represents an oxygen atom or a sulfur atom;

m represents an integer of 2 to 14; and

n represents an integer of 2 to 7;

or enantiomers of the compound, or hydrates or pharmaceuticallyacceptable salts of the compound or its enantiomers.

In addition, the present invention provides a pharmaceutical compositioncomprising a compound of general formula (1) as an active ingredient.Further, the present invention provides an anti-estrogenicpharmaceutical composition comprising the above compound as an activeingredient. The present invention also provides a therapeutic agent forbreast cancer comprising the above compound as an active ingredient.

A butyl group as R₁ encompasses a n-butyl group, an i-butyl group, as-butyl group and a t-butyl group, with a n-butyl group and an i-butylgroup being preferred.

In the definition of a compound having general formula (1), R₁ maypreferably be an ethyl group, a n-propyl group or a n-butyl group.

Salt-forming metals as R₂ include, but are not limited to, alkali metalssuch as sodium and potassium, alkaline earth metals such as magnesiumand calcium, rare earth metals such as cerium and samarium, as well aszinc and tin. Among these, preferred are alkali metals and alkalineearth metals, particularly sodium, potassium and calcium.

R₂ may preferably be a hydrogen atom, an alkali metal or an alkalineearth metal.

Halogens in the linear or branched C₁-C₇ halogenoalkyl groups as R₃include fluorine, chlorine, bromine and iodine, with fluorine beingpreferred. Alkyls in the linear or branched C₁-C₇ halogenoalkyl groupsunder consideration include, for example , methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl andn-heptyl. Preferred are linear or branched C₁-C₅ alkyls, morespecifically linear or branched C₂-C₄ alkyls, i.e., ethyl, n-propyl,i-propyl and n-butyl. Particularly preferred are ethyl and n-butyl.

Examples of the linear or branched C₁-C₇ halogenoalkyl group as R₃include the above-listed linear or branched C₁-C₇ alkyl groups, providedthat they are halogenated, preferably perhalogenated, more preferablyperfluorinated. Also preferred are perhalogenated linear or branchedC₁-C₅ alkyl groups, particularly perhalogenated linear or branched C₂-C₄alkyl groups, or a group of the following general formula (2):

in which each of R₆ and R₇ is a linear or branched C₁-C₃perhalogenoalkyl group. Among them, perfluorinated groups are preferred.More specifically, a perfluoroethyl group, a perfluoro-n-propyl groupand a perfluoro-n-butyl group are particularly preferred.

In the case where R₃ is a group of general formula (2), halogens in thelinear or branched C₁-C₃ perhalogenoalkyl groups as R₆ and R₇ includefluorine, chlorine, bromine and iodine, with fluorine being preferred.Alkyls in the linear or branched C₁-C₃ perhalogenoalkyl groups underconsideration include, methyl, ethyl, n-propyl and i-propyl, with methylbeing preferred.

In the case where R₃ is a group of general formula (2), examples of thelinear or branched C₁-C₃ perhalogenoalkyl group as R₆ and R₇ include theabove-listed linear or branched C₁-C₃ alkyl groups, provided that theyare perhalogenated, preferably perfluorinated. Further, perhalogenatedC₁ alkyl groups are preferred and a perfluorinated group is particularlypreferred. More specifically, a perfluoromethyl group is preferred.

A group of general formula (2) as R₃ is preferably a1,1,1,3,3,3-hexafluoroisopropyl group.

Having the definition given above, R₃ is preferably a perfluoroethylgroup, a perfluoro-n-propyl group, a perfluoro-n-butyl group or a1,1,1,3,3,3-hexafluoroisopropyl group.

Alkyls in the optionally substituted linear or branched C₁-C₃ alkylgroups as R₄ and R₅ include, methyl, ethyl, n-propyl and i-propyl.

Substituents on the optionally substituted linear or branched C₁-C₃alkyl groups as R₄ and R₅ include, an alkoxy group having a linear orbranched C₁-C₅ alkyl as its alkyl moiety and a hydroxyl group, morespecifically a methoxy group.

Examples of the optionally substituted linear or branched C₁-C₃ alkylgroup as R₄ and R₅ include the above-listed alkyl groups, provided thatthey may be substituted with the above-listed substituents. Specificexamples of the substituted alkyl group include a methoxymethyl group.

Examples of the acyl group as R₄ and R₅ include, an acetyl group, abenzoyl group and a pivaloyl group.

Salt-forming metals as R₄ and R₅ include, alkali metals such as sodiumand potassium, alkaline earth metals such as magnesium and calcium, rareearth metals such as cerium and samarium, as well as zinc and tin. Amongthese, preferred are alkali metals and alkaline earth metals,particularly sodium, potassium and calcium.

Preferably, R₄ and R₅ are independently a hydrogen atom or asalt-forming metal. In a suitable combination of R₂, R₄ and R₅, at leastone or all of them may be a hydrogen atom and the remainder may be asalt-forming metal. Examples of such combination include the following:a combination where R₂, R₄ and R₅ are each a hydrogen atom; acombination where R₂ is a salt-forming metal (e.g., an alkali metal suchas sodium) and R₄ and R₅ are each a hydrogen atom; and a combinationwhere R₂, R₄ and R₅ are each a salt-forming metal (e.g., an alkali metalsuch as sodium).

X may preferably be an oxygen atom or a sulfur atom.

m may preferably be an integer of 6 to 10, particularly 8 to 10, moreparticularly 8 or 9.

n may preferably be an integer of 2 to 6, particularly 2 to 5.

Compounds of general formula (1) have enantiomers. All individualenantiomers and mixtures thereof are intended to be within the scope ofthe present invention. Among the enantiomers, preferred are compoundswhere the configuration of 3- and 4-position chiral carbons in theparent scaffold (i.e., chroman or thiochroman ring) in general formula(1) is (3RS,4RS), (3R,4R) or (3S,4S). Also compounds having R- orS-configuration at the carbon to which the carboxylic acid is bonded,wherein said carbon is the carbon on the side chain which is bonded to4-position of the parent scaffold (i.e., chroman or thiochroman ring) ingeneral formula (1) and mixtures of such compounds at any ratio arepreferable.

Among compounds of general formula (1), preferred are those compounds inwhich R₁ is an ethyl group, a n-propyl group or a n-butyl group; R₂ is ahydrogen atom, an alkali metal or an alkaline earth metal; R₃ is aperfluoroethyl group, a perfluoro-n-propyl group, a perfluoro-n-butylgroup or a 1,1,1,3,3,3-hexafluoroisopropyl group; X is an oxygen atom ora sulfur atom; m is an integer of 8 or 9; and n is an integer of 2 to 6.Particularly preferred are compounds in which:

a) R₁ is an ethyl group; R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 8, and n is 3;

b) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 8, and n is 4;

c) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 8, and n is 5;

d) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is a sulfur atom, m is 8, and n is 2;

e) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 9, and n is 3;

f) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is a sulfur atom, m is 9, and n is 2;

g) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 8, and n is 3;

h) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is an oxygen atom, m is 9, and n is 5;

i) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 9, and n is 2;

j) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 8, and n is 3;

k) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 9, and n is 3;

l) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 8, and n is 4;

m) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is a sulfur atom, m is 8, and n is 2;

n) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is a sulfur atom, m is 9, and n is 3;

o) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is a sulfur atom, m is 9, and n is 2;

p) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is an oxygen atom, m is 8, and n is 4;

q) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 8, and n is 2;

s) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 8, and n is 3;

t) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is an oxygen atom, m is 9, and n is 3;

u) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is an oxygen atom, m is 9, and n is 4;

v) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 9, and n is 2;

w) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 9, and n is 3;

x) R₁ is a n-butyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 8, and n is 3; or

y) R₁ is a n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 8, and n is 3.

The compounds of the present invention may be obtained as hydrates.

As typical examples of these compounds, the following compounds can bementioned:

10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid;

10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid;

10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid;

11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;

11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoicacid;

11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid;

10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid;

11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5,-pentafluoropentyl)undecanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid;

11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid;

10-[(3RS,4RS)-3-butyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid;

10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

As an optically active compound of general formula (1) that has chiralcarbons at positions 3 and 4 of the parent scaffold and at α-position tothe carboxyl group of the side chain, each of the compounds representedby Peaks 1 and 2 in Examples 50 and 52 stated below is preferred.

Pharmaceutically acceptable salts include, the above-mentioned metalsalts, for example, sodium, potassium and calcium salts. Such metalsalts may be formed with a carboxyl group and/or a phenolic hydroxylgroup in the compound of the present invention.

The compound of general formula (1) may be administered as apharmaceutical composition in any dosage form suitable for the intendedroute of administration, in combination with one or morepharmaceutically acceptable diluents, wetting agents, emulsifiers,dispersants, auxiliary agents, preservatives, buffers, binders,stabilizers and the like. The compound and composition may beadministered parenterally or orally.

The dose of the compound can be suitably determined according to thephysique, age and physical condition of a patient, severity of thedisease to be treated, elapsed time after onset of the disease, etc. Forexample, the compound is generally used in an amount of 0.1 to 500mg/day when orally administered and in an amount of 1 to 1000 mg/monthwhen parenterally administered (by intravenous, intramuscular, orsubcutaneous route) for adult patient.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of general formula (1) can be prepared according to any oneof the following Reaction Schemes 1 to 10 (Processes 1 to 10).

In the above Reaction Scheme 1 (Process 1), R₁, R₃, X, m and n are asdefined above in general formula (1); each of R₁₁, R₁₂ and R₁₃represents a protecting group; each of L₁ and L₂ represents a leavinggroup; and m₁ equals m-2.

In the above Reaction Scheme 2 (Process 2), R₁, R₃, X, m and n are asdefined above in general formula (1); and R₁₁ represents a protectinggroup.

In the above Reaction Scheme 3 (Process 3), R₁, R₃, X, m and n are asdefined above in general formula (1); each of R₁₁ and R₁₃ represents aprotecting group; and L₁ represents a leaving group.

In the above Reaction Scheme 4 (Process 4), R₁, R₃, X, m and n are asdefined above in general formula (1); each of R₁₁ and R₁₃ represents aprotecting group; and m₃+3 equals m.

In the above Reaction Scheme 5 (Process 5), R₁, R₃, X, m and n are asdefined above in general formula (1); each of R₁₁ and R₁₃ represents aprotecting group; and m₃+3 equals m.

The preparation of the compounds according to the present invention willbe illustrated below in more detail, in line with the above-mentionedreaction schemes.

Process 1

In the presence of a base (e.g., n-butyllithium, s-butyllithium, sodiumhydride), compound (I) is reacted with alkyne (II) in an inert solvent(e.g., tetrahydrofuran, diethyl ether, dioxane, dichloromethane,chloroform, preferably tetrahydrofuran or dioxane) at a temperatureranging from −78° C. to the boiling point of the reaction mixture,preferably from −78° C. to room temperature, to give compound (III).

In the presence of a Lewis acid such as zinc iodide, compound (III) isreduced with sodium cyanoborohydride (NaBH₃CN) in an inert solvent(e.g., tetrahydrofuran, diethyl ether, dioxane, dichloromethane,dichloroethane or chloroform, preferably dichloroethane) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably from 0° C. to room temperature, to give compound(IV).

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide), compound (IV) is hydrogenated in an inertsolvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran,dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperatureranging from room temperature to the boiling point of the reactionmixture, preferably at room temperature, to give compound (V). Compound(V) can be directly prepared from compound (III) through hydrogenationusing a catalyst (e.g., palladium on activated carbon, palladiumhydroxide or platinum oxide) in an inert solvent (e.g., methanol,ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferablytetrahydrofuran, ethyl acetate) at a temperature ranging from roomtemperature to the boiling point of the reaction mixture, preferably atroom temperature.

Compound (V) is subjected to deprotection of the alcoholic hydroxylgroup in an inert solvent to give compound (VI).

In the presence of a base (e.g., triethylamine or pyridine), compound(VI) is treated with methanesulfonyl chloride or p-toluenesulfonylchloride in an inert solvent (e.g., tetrahydrofuran, dioxane,dichloromethane, dichloroethane or chloroform, preferablydichloromethane) at a temperature ranging from room temperature to theboiling point of the reaction mixture, preferably at room temperature,to convert (CH₂)_(m)OH in compound (VI) into (CH₂)_(m)—O—SO₂CH₃ or(CH₂)_(m)—O—SO₂—C₆H₄—p—CH₃. The compound thus obtained is then treatedwith a metal halide (e.g., sodium iodide or potassium iodide) in aninert solvent (e.g., acetone, tetrahydrofuran, dioxane, dichloromethane,dichloroethane or chloroform, preferably acetone) at a temperatureranging from room temperature to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (VII).

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (VII) is reacted with a malonic ester offormula (VIII) (e.g., diethyl malonate or dimethyl malonate) in an inertsolvent (e.g., tetrahydrofuran, dioxane, dimethylformamide,dichloromethane, dichloroethane or chloroform, preferablytetrahydrofuran) at a temperature ranging from room temperature to theboiling point of the reaction mixture to give compound (IX).

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (IX) is reacted with an alkylating agentof formula (X) in an inert solvent (e.g., tetrahydrofuran, diethylether, dioxane, dimethylformamide, dichloromethane, dichloroethane orchloroform, preferably tetrahydrofuran) at a temperature ranging fromroom temperature to the boiling point of the reaction mixture to givecompound (XI).

Compound (XI) is treated with sodium hydroxide or potassium hydroxide ina solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or awater/methanol mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (XII).

In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene,toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in thepresence of an acid (e.g., hydrogen chloride, sulfuric acid orp-toluenesulfonic acid), compound (XII) is heated to a temperatureranging from 50° C. to the boiling point of the reaction mixture to givecompound (XIII).

Next, compound (XIII) is subjected to deprotection of the phenolichydroxyl group to give compound (XIV).

Process 2

Compound (XIV) may also be synthesized from compound (XII) in thefollowing manner. A procedure analogous to Process 1 is repeated untilcompound (XII) is prepared.

Compound (XII) is subjected to deprotection of the phenolic hydroxylgroup to give compound (XV).

In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene,toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in thepresence of an acid (e.g., hydrogen chloride, sulfuric acid orp-toluenesulfonic acid), compound (XV) is heated to a temperatureranging from 50° C. to the boiling point of the reaction mixture to givecompound (XIV).

Process 3

Compound (XIV) can also be prepared from compound (VII) in the followingmanner.

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (VII) is reacted with compound (XVI) inan inert solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide,dichloromethane, dichloroethane or chloroform, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture to give compound (XI).

Compound (XI) is converted into compound (XIV) as in Process 1 or 2.

Process 4

Compound (XIV) may also be prepared in the following manner.

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XVII) is reacted with compound (XVIII) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XIX).

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide or Wilkinson's catalyst), compound (XIX) ishydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane or benzene) at a temperature rangingfrom room temperature to the boiling point of the reaction mixture,preferably at room temperature, to give compound (XX).

Compound (XX) is converted into compound (XIV) as in Process 1 or 2where compound (XI) is converted into compound (XIV).

Process 5

Further, compound (XIV) may also be prepared in the following manner.

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XVII) is reacted with compound (XXI) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XXII).

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide or Wilkinson's catalyst), compound (XXII) ishydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane orbenzene) at a temperature ranging from room temperature to the boilingpoint of the reaction mixture, preferably at room temperature, to givecompound (XXIII).

Compound (XXIII), which is identical with compound (XI) in Process 1, isconverted into compound (XIV) as in Process 1 or 2 where compound (XI)is converted into compound (XIV).

Compound (XVII) used in Processes 4 and 5 can be prepared by eitherProcess 6 or 7 shown below.

In the above Reaction Scheme 7 (Process 7), X is as defined above ingeneral formula (1); R₁₁ represents a protecting group; and L₃represents a leaving group.

Process 6 Preparation of Compound (XVII)—Part I

Compound (I) is reduced with lithium aluminum hydride ordiisobutylaluminum hydride in an inert solvent (e.g., diethyl ether,benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperatureranging from −78° C. to the boiling point of the reaction mixture togive compound (XXIV).

In the presence of a Lewis acid such as zinc iodide, compound (XXIV) isreacted with allyltrimethylsilane in an inert solvent (e.g.,tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform,preferably dichloroethane) at a temperature ranging from −78° C. to theboiling point of the reaction mixture, preferably from 0° C. to roomtemperature, to give compound (XVII).

Process 7 Preparation of Compound (XVII)—Part II

In the presence of anhydrous TBAF and, if necessary, accompanied byaddition of HMPA, compound (XXV) is reacted with allyltrimethylsilane inan inert solvent (e.g., dimethylformamide, dimethyl sulfoxide,tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform)at a temperature ranging from −78° C. to the boiling point of thereaction mixture, preferably from 0° C. to room temperature, to givecompound (XXVI).

In the presence of a base (e.g., lithium hexamethyl-disilazide,n-butyllithium, s-butyllithium, sodium hydride), compound (XXVI) isreacted with an alkylating agent (R₁-L₃) in an inert solvent (e.g.,tetrahydrofuran, ether, dioxane, dichloromethane, chloroform, preferablytetrahydrofuran or dioxane) at a temperature ranging from −78° C. to theboiling point of the reaction mixture, preferably from −78° C. to roomtemperature, to give compound (XXVII).

Compound (XXVII) is reduced with lithium aluminum hydride in an inertsolvent (e.g., tetrahydrofuran, dioxane or diethyl ether) at atemperature ranging from −78° C. to the boiling point of the reactionmixture to give compound (XXVIII).

Compound (XXVIII) is reacted with diethyl azodicarboxylate andtriphenylphosphine in an inert solvent (e.g., toluene, dioxane,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane,dichloroethane or chloroform) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably from 0° C. to roomtemperature, to give compound (XVII).

Compound (XIV) given by the above Processes 1 to 5 may also be convertedinto a salt form because it has a carboxyl group. Pharmaceuticallyacceptable salts include, sodium, potassium and calcium salts. Forexample, a salt of compound (XIV) can be prepared as follows.

Sodium methoxide is added to compound (XIV) dissolved in an organicsolvent (e.g., dry methanol) at an appropriate temperature, for example,at room temperature, and the resulting mixture is stirred for about 30minutes to about 3 hours at the same temperature. After addition of anorganic solvent such as dry diethyl ether, the reaction mixture isevaporated under reduced pressure to remove the solvent, therebyobtaining a salt of the compound.

The compound of the present invention exists as various enantiomersbecause it contains three asymmetric carbon atoms. To obtain a singlestereoisomer, there are two techniques, one of which uses a chiralcolumn to resolve a mixture of stereoisomers and the other involvesasymmetric synthesis. The chiral column technique may be carried outusing a column commercially available from DAICEL under the trade nameof CHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OC, OD, OFor OG, for example. Regarding asymmetric synthesis, the following willillustrate the asymmetric synthesis of the inventive compound withrespect to an asymmetric carbon atom, to which a side chain carboxylgroup is attached.

Process 8

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XXIX) is reacted with compound (XXX) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XXXI).

Compound (XXXI) is then subjected to the following reactions in theorder stated, (a) reduction, deprotection and hydrolysis or (b)reduction, hydrolysis and deprotection, to give compound (XXXII).

(a) Reduction, Deprotection and Hydrolysis

1) Reduction

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound(XXXI) is hydrogenated in an inert solvent (e.g., methanol, ethanol,ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably at room temperature, to give a reduction product.

2) Deprotection

Next, deprotection of the phenolic hydroxyl group is carried out to givea deprotected product.

3) Hydrolysis

By way of example, if R* is a group of formula (XXXVIII), thedeprotected product is further treated with lithium hydroxide, sodiumhydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxideplus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogenperoxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethylether/water mixture, a dioxane/water mixture, a methanol/water mixture,an ethanol/water mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at roomtemperature, to give compound (XXXII).

(b) Reduction, Hydrolysis and Deprotection

1) Reduction

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound(XXXI) is hydrogenated in an inert solvent (e.g., methanol, ethanol,ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably at room temperature, to give a reduction product.

2) Hydrolysis

By way of example, if R* is a group of formula (XXXVIII), the reductionproduct is further treated with lithium hydroxide, sodium hydroxide,lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogenperoxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in asolvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/watermixture, a dioxane/water mixture, a methanol/water mixture, anethanol/water mixture) at a temperature ranging from room temperature tothe boiling point of the reaction mixture, preferably at roomtemperature, to give a carboxylic acid.

3) Deprotection

Next, deprotection of the phenolic hydroxyl group is carried out to givecompound (XXXII).

Process 9

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound(XXIX) is reacted with compound (XXXIII) in a solvent (e.g., methylenechloride, chloroform, benzene, toluene, xylene, dioxane,tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound (XXXIV).

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound(XXXIV) is hydrogenated in an inert solvent (e.g., methanol, ethanol,ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably at room temperature, to give a reduction product.

Next, deprotection of the phenolic hydroxyl group is carried out to givecompound (XXXII).

The chiral olefins of formulae (XXX) and (XXXIII) used in the aboveProcesses 8 and 9, respectively, may be synthesized as follows.

In the above Reaction Schemes 8, 9 and 10 (Processes 8, 9 and 10), R₁,R₃, X, m and n are as defined above in general formula (1); R*represents a chiral auxiliary group; P represents a leaving group; Lrepresents a leaving group; and m₂ and m₃ are integers that satisfy therelation m=m₂+m₃+2. The symbol R in formula (XXXIV) represents an alkylgroup.

Synthesis of Chiral Olefins

In the presence of a base (e.g., lithium diisopropylamide, lithiumhexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) andHMPA, compound (XXXV) is reacted with R₃(CH₂)_(n)—L in an inert solvent(e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture, preferably from −30° C. to roomtemperature, to give compound (XXX).

Alternatively, in the presence of a base (e.g., lithiumdiisopropylamide, lithium hexamethyl-disilazide, sodiumhexamethyl-disilazide, butyllithium) and HMPA, compound (XXXVI) isreacted with compound (XXXVII) in an inert solvent (e.g.,tetrahydrofuran, toluene, diethyl ether, hexane, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture, preferably from −30° C. to roomtemperature, to give compound (XXX).

In the presence of a nucleophilic reagent (e.g., lithium hydroxide plushydrogen peroxide, lithium hydroxide, sodium methoxide, sodiumthioethoxide) or an acid (e.g., hydrochloric acid, sulfuric acid),compound (XXX) is hydrolyzed in an inert solvent (e.g., methanol,ethanol, tetrahydrofuran, water, preferably a tetrahydrofuran/watermixture) at a temperature ranging from −78° C. to the boiling point ofthe reaction mixture, preferably from room temperature to 50° C., toconvert the chiral auxiliary group R* into OH.

In the case where each of R₄ and R₅ is an acyl group or an alkyl group,the synthesis can be carried out according to Process 9.

EXAMPLES

The present invention is more specifically explained by the followingexamples. However, it should be understood that the present invention isnot limited to these examples in any manner. In order to explain theeffectiveness of the compounds according to the present invention,typical compounds were tested for their anti-estrogenic activity in thetest example shown below. Tables 1 and 2 show chemical structures of thecompounds prepared in the Examples.

TABLE 1

Example No. X R₁ R₂ R₃ R₄ R₅ m n 13 S Et H —CF₂CF₃ H H 8 6 14 S Et H—CF₂CF₃ H H 5 15 S Et H —CF₂CF₃ H H 4 16 S Et H —CF₂CF₃ H H 3 31 S Et H—(CF₂)₃CF₃ H H 2 17 S Et H —CF₂CF₃ H H 9 6 18 S Et H —CF₂CF₃ H H 5 19 SEt H —CF₂CF₃ H H 4 20 S Et H —CF₂CF₃ H H 3 30 S Et H —(CF₂)₃CF₃ H H 2 25O Et H —CF₂CF₃ H H 8 6 26 O Et H —CF₂CF₃ H H 5 27 O Et H —CF₂CF₃ H H 428 O Et H —CF₂CF₃ H H 3 33 O Et H —(CF₂)₃CF₃ H H 2 21 O Et H —CF₂CF₃ H H9 6 22 O Et H —CF₂CF₃ H H 5 23 O Et H —CF₂CF₃ H H 4 24 O Et H —CF₂CF₃ HH 3 32 O Et H —(CF₂)₃CF₃ H H 2 29 S n-Pr H —CF₂CF₃ H H 8 3

TABLE 2

Example No. X R₁ R₂ R₃ R₄ R₅ m n 34 O Et H —(CF₂)₃CF₃ H H 8 3 35 O Et H—(CF₂)₃CF₃ H H 9 3 36 S n-Pr H —CF₂CF₃ H H 8 4 37 S n-Pr H —(CF₂)₃CF₃ HH 8 2 38 S n-Pr H —CF₂CF₃ H H 9 3 39 S n-Pr H —(CF₂)₃CF₃ H H 9 2 40 On-Pr H —CF₂CF₃ H H 8 4 41 O n-Pr H —(CF₂)₃CF₃ H H 8 2 42 O n-Pr H—(CF₂)₃CF₃ H H 8 3 43 O n-Pr H —CF₂CF₃ H H 9 3 44 O n-Pr H —CF₂CF₃ H H 94 45 O n-Pr H —(CF₂)₃CF₃ H H 9 2 46 O n-Pr H —(CF₂)₃CF₃ H H 9 3 47 On-Bu H —(CF₂)₃CF₃ H H 8 3 50, Peak 1 O n-Pr H —(CF₂)₃CF₃ H H 8 3 50,Peak 2 O n-Pr H —(CF₂)₃CF₃ H H 8 3 52, Peak 1 O n-Pr H —(CF₂)₃CF₃ H H 83 52, Peak 2 O n-Pr H —(CF₂)₃CF₃ H H 8 3

Example 1 Synthesis of 1-iodo-4,4,5,5,5-pentafluoropentane

Trietylamine (46 ml, 0.330 mol) was added to a solution of4,4,5,5,5-pentafluoropentan-1-ol (25 g, 0.132 mol) in dichloromethane(50 ml). To this solution, methanesulfonyl chloride (20.4 ml, 0.264 mol)was added at 0° C., followed by stirring for 3 hours at room temperatureunder argon atmosphere. After the reaction was completed, water wasadded to the reaction mixture, which was then extracted withdichloromethane. The organic layer was washed with 1N aqueoushydrochloric acid, water and saturated aqueous sodium chloride, and thendried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was purified by silica gel flash columnchromatography (eluent: hexane/ethyl acetate=1/1) to give1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (34 g, quantitative).

¹H-NMR (300 MHz, CDCl₃): d 4.30 (t, 2H), 3.05 (s, 3H), 2.30-2.05 (m,4H).

Sodium iodide (35.1 g, 2.15 mol) was added to a solution of1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (20 g, 0.781 mol) inacetone (200 ml), followed by heating under reflux for 12 hours. Afterthe reaction mixture was filtered, the filtrate was concentrated. Ethylacetate was added to the residue, which was then filtered again. Thefiltrate was washed with water and saturated aqueous sodium chloride,and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off to give 1-iodo-4,4,5,5,5-pentafluoropentane (21.1 g, Yield93.4%).

¹H-NMR (300 MHz, CDCl₃): d 3.22 (t, 2H, J=6.8 Hz), 2.28-2.10 (m, 4H).

Example 2 Synthesis of 1-Iodo-5,5,6,6,6-pentafluorohexane

1-Methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (138 g, 538.62 mmol)was dissolved in dimethyl sulfoxide (1000 ml). Sodium cyanide (55.57 g,1.077 mol) and 18-crown-6 (2.85 g, 10.77 mmol) were added to thesolution followed by stirring for 2 hours at 100° C. After cooling toroom temperature, water was added to the reaction mixture, which wasthen extracted twice with ether. The combined organic layers were washedwith water and saturated aqueous sodium chloride, and then dried overanhydrous magnesium sulfate. The solvent was distilled off to give5,5,6,6,6-pentafluorohexanecarbonitrile (108 g, Yield 100%).

¹H-NMR (300 MHz, CDCl₃): δ 2.47 (t, 2H), 2.26-2.11 (m, 2H), 2.02-1.93(m, 2H).

Concentrated sulfuric acid (350 ml) was slowly added dropwise to5,5,6,6,6-pentafluorohexanecarbonitrile (108 g, 577.20 mmol) at 0° C.,and the resulting mixture was stirred for 3 hours at room temperature.Water (350 ml) was slowly added dropwise to this mixture at 0° C.,followed by heating under reflux for 12 hours. After cooling to roomtemperature, water was added to the reaction mixture, which was thenextracted three times with dichloromethane. The combined organic layerswere washed with water and saturated aqueous sodium chloride, and thendried over anhydrous magnesium sulfate. The solvent was distilled off togive 5,5,6,6,6-pentafluorohexanoic acid (95.8 g, Yield 85%).

¹H-NMR (300 MHz, CDCl₃): δ 2.45 (t, 2H, J=7.1 Hz), 2.23-2.09 (m, 2H),2.01-1.92 (m, 2H).

5,5,6,6,6-Pentafluorohexanoic acid (95 g, 460.92 mmol) was dissolved inanhydrous tetrahydrofuran (1L) and cooled to −30° C. To this solution,borane-methyl sulfide complex (10 M in THF, 92.2 ml, 921.84 mmol) wasslowly added dropwise, followed by stirring for 3 hours at roomtemperature. After treatment with methanol at 0° C., water was added tothe reaction mixture, which was then extracted twice with ether. Thecombined organic layers were washed with water and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the resulting residue was dissolved indichloromethane (1500 ml), and triethylamine (160.6 ml, 1.15 mol) andmethanesulfonyl chloride (46.4 ml, 599.19 mmol) were added dropwisethereto at 0° C., followed by stirring for 1 hour. After the reactionwas completed, water was added to the reaction mixture, which was thenextracted twice with dichloromethane. The combined organic layers werewashed with water and saturated aqueous sodium chloride, and then driedover anhydrous magnesium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/4) to give1-methanesulfonyloxy-5,5,6,6,6-pentafluorohexane (101 g, Yield 81%).

¹H-NMR (300 MHz, CDCl₃): δ 4.24 (t, 2H, J=6.0 Hz), 2.98 (s, 3H),2.19-2.00 (m, 2H), 1.93-1.67 (m, 4H).

Sodium iodide (168 g, 1.12 mol) was added to a solution of1-methanesulfonyloxy-5,5,6,6,6-pentafluorohexane (101 g, 373.77 mmol) inacetone (2000 ml), followed by heating under reflux for 12 hours. Waterwas added to the reaction mixture, which was then extracted twice withether. The combined organic layers were washed with 1% aqueous sodiumthiosulfate and saturated aqueous sodium chloride, and then dried overanhydrous magnesium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (eluent:pentane) to give 1-iodo-5,5,6,6,6-pentafluorohexane (93.6 g, Yield 83%).

¹H-NMR (300 MHz, CDCl₃): δ 3.20 (t, 2H, J=6.9 Hz), 2.27-1.87 (m, 4H),1.78-1.69 (m, 2H).

Example 3 Synthesis of 1-Iodo-6,6,7,7,7-pentafluoroheptane

Sodium hydride (60%, 2.87 g, 71.87 mmol) was added to anhydroustetrahydrofuran (250 ml) and cooled to 0° C. To this mixture, diethylmalonate (12.12 ml, 79.86 mmol) was slowly added dropwise, followed bystirring for 1 hour at room temperature.1-Iodo-4,4,5,5,5-pentafluoropentane (11.5 g, 39.93 mmol) dissolved inanhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to thereaction mixture, followed by stirring for 12 hours at room temperature.Water was added to the reaction mixture, which was then extracted twicewith ethyl acetate. The combined organic layers were washed with waterand saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/40) to give diethyl2-(4,4,5,5,5-pentafluoropentyl)malonate (11.2 g, Yield 88%).

¹H-NMR (300 MHz, CDCl₃): δ 4.21 (m, 4H), 3.34 (t, 1H, J=7.27), 2.09-1.94(m, 4H), 1.68-1.62 (m, 2H), 1.27 (t, 6H, J=7.15 Hz).

A solution of potassium hydroxide (370 g, 6.6 mol) in water (500 ml) wasadded to a solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate(105.3 g, 0.33 mol) in ethanol (1000 ml), followed by stirring for 16hours at 60° C. The reaction mixture was adjusted to pH 5 by slowlyadding 1N hydrochloric acid dropwise, and then extracted twice withethyl acetate. The combined organic layers were washed with saturatedaqueous sodium chloride and dried over anhydrous magnesium sulfate.After distilling off the solvent, the residue was dissolved in dimethylsulfoxide (500 ml) and stirred for 18 hours at 170° C. Water was addedto the reaction mixture, which was then extracted three times with ethylacetate. The combined organic layers were washed with water andsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the residue wasdissolved in anhydrous tetrahydrofuran (300 ml) and cooled to −30° C.Borane-methyl sulfide complex (10 M in THF, 55 ml, 0.55 mol) was slowlyadded dropwise to the solution, followed by stirring for 3 hours at roomtemperature. After treatment with methanol at 0° C., water was added tothe reaction mixture, which was then extracted twice with ethyl acetate.The combined organic layers were washed with water and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/20) to give6,6,7,7,7-pentafluoroheptan-1-ol (39 g, Yield 57%).

¹H-NMR (300 MHz, CDCl₃): δ 3.66 (t, 2H), 2.17-1.94 (m, 2H), 1.68-1.53(m, 4H), 1.53-1.41 (m, 2H).

Triethylamine (25.83 ml, 185.3 mmol) and methanesulfonyl chloride (6.9ml, 88.9 mmol) were added dropwise to a solution of6,6,7,7,7-pentafluoroheptan-1-ol (14.1 g, 74.1 mmol) in dichloromethane(350 ml) at 0° C., followed by stirring for 1 hour. After the reactionwas completed, water was added to the reaction mixture, which was thenextracted twice with dichloromethane. The combined organic layers werewashed with water and saturated aqueous sodium chloride, and then driedover anhydrous magnesium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/10) to give1-methanesulfonyloxy-6,6,7,7,7-pentafluoroheptane (17.3 g, Yield 82%).

¹H-NMR (300 MHz, CDCl₃): δ 4.24 (t, 2H), 3.01 (s, 3H), 2.13-1.96 (m,2H), 1.85-1.76 (m, 2H), 1.70-1.47 (m, 4H).

Sodium iodide (27.37 g, 182.58 mmol) was added to a solution of1-methanesulfonyloxy-6,6,7,7,7-pentafluoroheptane (17.3 g, 60.86 mmol)in acetone (500 ml), followed by heating under reflux for 12 hours.Water was added to the reaction mixture, which was then extracted twicewith ether. The combined organic layers were washed with 1% aqueoussodium thiosulfate and saturated aqueous sodium chloride, and then driedover anhydrous magnesium sulfate. The solvent was distilled off to give1-iodo-6,6,7,7,7-pentafluoroheptane (16.5 g, Yield 86%).

¹H-NMR (300 MHz, CDCl₃): δ 3.20 (t, 2H), 2.11-1.98 (m, 2H), 1.92-1.83(m, 2H), 1.63-1.50 (m, 4H).

Example 4 Synthesis of 1-Iodo-7,7,8,8,8-Pentafluorooctane

7,7,8,8,8-Pentafluorooctan-1-ol (25 g, 113 mmol) was dissolved indichloromethane (250 ml) and cooled to 0° C. To this solution,triethylamine (47.4 ml, 339 mmol) and methanesulfonyl chloride (17.6 ml,227 mmol) were added dropwise, followed by stirring for 1 hour. Afterthe reaction was completed, water was added to the reaction mixture,which was then extracted twice with dichloromethane. The combinedorganic layers were washed with water and saturated aqueous sodiumchloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/10) to give1-methanesulfonyloxy-7,7,8,8,8-pentafluorooctane (30 g, Yield 89%).

¹H-NMR (300 MHz, CDCl₃): δ 4.24 (t, 2H), 3.01 (s, 3H), 2.13-1.96 (m,2H), 1.85-1.76 (m, 2H), 1.70-1.47 (m, 6H).

Sodium iodide (19.62 g, 130 mmol) was added to a solution of1-methanesulfonyloxy-7,7,8,8,8-pentafluorooctane (14 g, 47.01 mmol) inacetone (200 ml), followed by heating under reflux for 12 hours. Afterthe reaction was completed, water was added to the reaction mixture,which was then extracted twice with ether. The combined organic layerswere washed with 1% aqueous sodium thiosulfate and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off to give 1-iodo-7,7,8,8,8-pentafluorooctane (14g, Yield 89%).

¹H-NMR (300 MHz, CDCl₃): δ 3.15 (t, 2H), 2.14-1.97 (m, 2H), 1.85-1.75(m, 2H), 1.70-1.51 (m, 2H), 1.45-1.31 (m, 4H).

Example 5 Synthesis of Ethyl 2-(5,5,6,6,6-Pentafluorohexyl)-9-decenoate

Sodium hydride (60%, 6.3 g, 156.96 mmol) was added to anhydroustetrahydrofuran (200 ml) under argon atmosphere and cooled to 0° C. Tothis mixture, diethyl malonate (23.8 ml, 156.95 mmol) was slowly addeddropwise, followed by stirring for 1 hour at room temperature. Aftercooling to 0° C., 8-bromo-1-octene (20 g, 104.64 mmol) was slowly addedto the reaction mixture, followed by stirring for 12 hours at roomtemperature. Water was added to the reaction mixture, which was thenextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride and dried over magnesium sulfate.After distilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/30) to givediethyl 2-(7-octenyl)malonate (16 g, Yield 56.56%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 5.77 (m, 1H), 5.03-4.83 (m, 2H), 4.17 (q, 4H,J=6.8 Hz), 3.30 (t, 1H, J=7.6 Hz), 2.04-2.00 (m, 2H), 1.98-1.83 (m, 2H),1.38-1.23 (m, 14H).

Sodium hydride (60%, 326 mg, 8.14 mmol) was added to dimethyl sulfoxide(5 ml) under argon atmosphere and cooled to 0° C. To this mixture,diethyl 2-(7-octeny)malonate (2 g, 7.40 mmol) dissolved in dimethylsulfoxide (5 ml) was slowly added, followed by stirring for 1 hour.After cooling to 0° C., 1-iodo-5,5,6,6,6-pentafluorohexane (2.68 g, 8.88mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added to thereaction mixture, followed by stirring for 2 hours at room temperature.Water was added to the reaction mixture, which was then extracted withethyl acetate. The organic layer was washed with water and dried overmagnesium sulfate. After distilling off the solvent, the residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/20) to give diethyl2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.3 g, Yield 70%)as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 5.78 (m, 1H), 5.05-4.85 (m, 2H), 4.19 (q, 4H,J=7.1 Hz), 2.04-1.95 (m, 4H), 1.90-1.80 (m, 4H), 1.65-1.59 (m, 2H),1.38-1.12 (m, 16H).

Lithium chloride (401 mg, 9.540 mmol) and water (86 mg, 4.770 mmol) wereadded to a solution of diethyl2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.12 g, 4.770mmol) in dimethyl sulfoxide (8 ml) followed by stirring for 16 hours at180° C. After cooling, water was added to the reaction mixture, whichwas then extracted with ethyl acetate. The organic layer was washed withwater and saturated aqueous sodium chloride, and then dried overanhydrous magnesium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/50) to give ethyl2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate (1.40 g, Yield 79%) as acolorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 5.79 (m, 1H), 5.04-4.84 (m, 2H), 4.15 (q, 2H,J=7.2 Hz), 2.30 (m, 1H), 2.06-1.97 (m, 4H), 1.66-1.52 (m, 4H), 1.49-1.23(m, 15H).

Example 6 Synthesis of Ethyl 2-(4,4,5,5,5-Pentafluoropentyl)-9-decenoate

Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5and the 1-iodo-4,4,5,5,5-pentafluoropentane prepared in Example 1, thesame procedure as shown in Example 5 was repeated to give ethyl2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate.

¹H-NMR (300 MHz, CDCl₃): δ 5.80 (m, 1H), 4.97 (m, 2H), 4.15 (q, 2H,J=7.1 Hz), 2.34 (m, 1H), 2.02 (m, 4H), 1.75-1.26 (m, 17H).

Example 7 Synthesis of Ethyl 2-(6,6,7,7,7-Pentafluoroheptyl)-9-decenoate

Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5and the 1-iodo-6,6,7,7,7-pentafluoroheptane prepared in Example 3, thesame procedure as shown in Example 5 was repeated to give ethyl2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate.

¹H-NMR (300 MHz, CDCl₃): δ 5. 78 (m, 1H), 5. 00 (m, 2H), 4.12 (q, 2H),2.30 (m, 1H), 2.07-1.93 (m, 4H), 1.64-1.49 (m, 4H), 1.47-1.20 (m, 17H).

Example 8 Synthesis of Ethyl 2-(7,7,8,8,8-Pentafluorooctyl)-9-decenoate

Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5and the 1-iodo-7,7,8,8,8-pentafluorooctane prepared in Example 4, thesame procedure as shown in Example 5 was repeated to give ethyl2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate.

¹H-NMR (300 MHz, CDCl₃): δ 5.78 (m, 1H), 5.02-4.88 (m, 2H), 4.10 (q,2H), 2.27 (m, 1H), 2.06-1.91 (m, 4H), 1.63-1.18 (m, 23H).

Example 9 Synthesis of Ethyl 2-(5,5,6,6,6-Pentafluorohexyl)-8-nonenoate

A solution of sodium hydroxide (13.67 g, 341.83 mmol) in water (100 ml)was added to a solution of 6-heptenyl acetate (17.8 g, 113.94 mmol) inmethanol (300 ml), followed by stirring for 2 hours at room temperature.The reaction mixture was neutralized with 10% hydrochloric acid andconcentrated under reduced pressure. Water was added to the residue,which was then extracted twice with ethyl acetate. The combined organiclayers were washed with water and saturated aqueous sodium chloride, andthen dried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was dissolved in dichloromethane (200 ml), andtriethylamine (33.57 ml, 240.83 mmol) and methanesulfonyl chloride (8.95ml, 115.60 mmol) were added dropwise thereto at 0° C., followed bystirring for 1 hour. Water was added to the reaction mixture, which wasthen extracted twice with dichloromethane. The combined organic layerswere washed with water and saturated aqueous sodium chloride, and thendried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was dissolved in acetone (370 ml) and mixed withsodium iodide (43.26 g, 288.64 mmol), followed by heating under refluxfor 12 hours. Water was added to this mixture, which was then extractedtwice with ether. The combined organic layers were washed with 1%aqueous sodium thiosulfate and saturated aqueous sodium chloride, andthen dried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was purified by silica gel column chromatography(eluent: pentane) to give 7-iodo-1-heptene (18 g, Yield 74%).

¹H-NMR (300 MHz, CDCl₃): δ 5.80 (m, 1H), 5.04-4.94 (m, 2H), 3.19 (t, 2H,J=6.9 Hz), 2.07-2.05 (m, 2H), 1.89-1.78 (m, 2H), 1.50-1.32 (m, 4H).

Sodium hydride (60%, 5.78 g, 144.59 mmol) was added to anhydroustetrahydrofuran (250 ml) and cooled to 0° C. To this mixture, diethylmalonate (25.09 g, 156.64 mmol) was slowly added dropwise, followed bystirring for 1 hour at room temperature. 7-Iodo-1-heptene (27 g, 120.49mmol) dissolved in anhydrous tetrahydrofuran (50 ml) was then slowlyadded dropwise to the mixture, followed by stirring for 12 hours at roomtemperature. Water was added to the reaction mixture, which was thenextracted twice with ethyl acetate. The combined organic layers werewashed with water and saturated aqueous sodium chloride, and then driedover anhydrous magnesium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/40) to give diethyl 2-(6-heptenyl)malonate (25.8 g,Yield 84%).

¹H-NMR (300 MHz, CDCl₃): δ 5.80 (m, 1H), 5.02-4.92 (m, 2H), 4.24-4.09(m, 4H), 3.31 (t, 1H, J=7.5 Hz), 2.07-2.00 (m, 2H), 1.93-1.85 (m, 2H),1.41-1.18 (m, 12H).

Starting with diethyl 2-(6-heptenyl)malonate and the1-iodo-5,5,6,6,6-pentafluorohexane prepared in Example 2, the sameprocedure as shown in Example 5 was repeated to give ethyl2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate.

¹H-NMR (300 MHz, CDCl₃): δ 5.80 (m, 1H), 5.22-4.91 (m, 2H), 4.14 (q, 2H,J=7.2 Hz), 2.39 (m, 1H), 2.10-1.93 (m, 4H), 1.67-0.83 (m, 17H).

Example 10 Synthesis of Ethyl2-(4,4,5,5,5-Pentafluoropentyl)-8-nonenoate

Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9and the 1-iodo-4,4,5,5,5-pentafluoro-pentane prepared in Example 1, thesame procedure as shown in Example 5 was repeated to give ethyl2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate.

¹H-NMR (300 MHz, CDCl₃): δ 5.78 (m, 1H), 5.10-4.90 (m, 2H), 4.14 (q, 2H,J=7.3 Hz), 2.31 (m, 1H), 2.15-1.90 (m, 4H), 1.70-1.08 (m, 15H); Mass(ESI): 345 (M+1).

Example 11 Synthesis of Ethyl2-(6,6,7,7,7-Pentafluoroheptyl)-8-nonenoate

Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9and the 1-iodo-6,6,7,7,7-pentafluoro-heptane prepared in Example 3, thesame procedure as shown in Example 5 was repeated to give ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate.

¹H-NMR (300 MHz, CDCl₃): δ 5.78 (m, 1H), 5.05-4.85 (m, 2H), 4.13 (q,2H), 2.31 (m, 1H), 2.08-1.90 (m, 4H), 1.63-1.50 (m, 4H), 1.48-1.15 (m,15H).

Example 12 Synthesis of Ethyl 2-(7,7,8,8,8-Pentafluorooctyl)-8-nonenoate

Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9and the 1-iodo-7,7,8,8,8-pentafluoro-octane prepared in Example 4, thesame procedure as shown in Example 5 was repeated to give ethyl2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate.

¹H-NMR (270 MHz, CDCl₃): d 5.88-5.71 (m, 1H, olefin-H), 5.03-4.90 (m,2H, olefin-H), 4.13 (q, J=9 Hz, 2H, COOCH₂), 2.30 (m, 1H, CHCOO),2.10-1.90 (m, 4H, CH₂CF₂ and allyl-CH₂), 1.55-1.22 (m, 21H, alkyl-H andCOOCH₂CH ₃).

Example 13 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)-decanoicAcid

7-Methoxy-3-(4-methoxyphenyl)thiochroman-4-one was synthesized by themethod described in WO98/25916 and a portion of this compound (26.73 g,89.1 mmol) was dissolved in toluene (900 ml), followed by addition ofethyl triflate (34.6 ml, 276 mmol). Potassium tert-butoxide (19.95 g,178 mmol) was added to this solution at 0° C. and the resulting mixturewas stirred for 2 days at room temperature under argon atmosphere.Potassium tert-butoxide (20.0 g, 178 mmol) was further added to thereaction mixture at 0° C., followed by stirring for 1 day. Water wasadded to the reaction mixture, which was then extracted with ether. Theether layer was washed with saturated aqueous sodium bicarbonate, waterand saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the residue waspurified by silica gel flash column chromatography (eluent: hexane/ethylacetate=5/1) to give3-ethyl-7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (26.12 g, Yield89%).

¹H-NMR (270 MHz, CDCl₃): δ 8.15 (d, J=9 Hz, 1H, Ar—H), 7.15 (d, J=9 Hz,2H, Ar—H), 6.82 (d, J=9 Hz, 2H, Ar—H), 6.67 (dd, J=9, 2 Hz, 1H, Ar—H),6.54 (d, J=2 Hz, 1H, Ar—H), 3.77 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 3.58(d, J=14 Hz, 1H, C2-H), 3.41 (d, J=14 Hz, 1H, C2-H), 2.04 (q, J=7 Hz,2H, CH ₂CH₃), 0.82 (t, 3H, J=7 Hz, 2H, CH₂CH ₃).

A solution of 3-ethyl-7-methoxy-3-(4-methoxyphenyl)-thiochroman-4-one(13.7 g, 41.8 mmol) in anhydrous tetrahydrofuran (100 ml) was addeddropwise to a solution of lithium aluminum hydride (950 mg, 25 mmol) inanhydrous tetrahydrofuran (100 ml) at −78° C. under argon atmosphere,and the resulting mixture was warmed to −20° C. over 1 hour. Ethylacetate, methanol and 2N aqueous hydrochloric acid were addedsequentially to the reaction mixture, which was then filtered throughcellite. After extraction with ethyl acetate, the organic layer waswashed with saturated aqueous sodium bicarbonate, water and saturatedaqueous sodium chloride, and then dried over anhydrous magnesiumsulfate. After distilling off the solvent, the resulting residue (13.10g) was dissolved in 1,2-dichloroethane (360 ml) and then mixed withallyltrimethylsilane (12.47 ml, 78.75 mmol). Zinc iodide (15.08 g, 47.27mmol) was added to this solution at 0° C. under argon atmosphere, andthe resulting mixture was stirred for 4 hours at 40° C. Water and dilutehydrochloric acid were added sequentially to this mixture, which wasthen extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate, water and saturated aqueous sodiumchloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gel flashcolumn chromatography (eluent: hexane/ethyl acetate=20/1) to give(3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)-4-(2-propenyl)thiochroman(8.73 g, Yield 62% for 2 steps).

¹H-NMR (270 MHz, CDCl₃): d 7.25 (d, J=9 Hz, 2H, Ar—H), 6.92 (d, J=9 Hz,2H, Ar—H), 6.90 (d, J=9 Hz, 1H, Ar—H), 6.71 (d, J=2 Hz, 1H, Ar—H), 6.55(dd, J=9, 2 Hz, 1H, Ar—H), 5.55 (m, 1H, olefin-H), 4.83 (d, J=10 Hz, 1H,olefin-H), 4.65 (d, J=17 Hz, 1H, olefin-H), 3.83 (s, 3H, OCH₃), 3.77 (s,3H, OCH₃), 3.48 (d, J=12 Hz, 1H, C2-H), 3.23 (d, J=12 Hz, 1H, C2-H),2.80 (m, 1H, C4-H), 1.90 (m, 2H, allylic-CH₂), 1.69 and 1.46 (each m,each 1H, CH ₂CH₃), 0.51 (t, 3H, J=7 Hz, 2H, C3-CH₂CH ₃).

The ethyl 2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate prepared in Example12 (1.67 g, 4.32 mmol) andbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium (90 mg, 0.11mmol) were added to a solution of(3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)-4-(2-propenyl)thiochroman(740 mg, 2.18 mmol) in dichloromethane (20 ml), followed by heatingunder reflux for 7.5 hours under argon atmosphere. After distilling offthe solvent under reduced pressure, the residue was purified by silicagel flash column chromatography (eluent: hexane/ethyl acetate=10/1) togive the desired olefin (1.15 g) as a mixture of cis- and trans-forms.This mixture was dissolved in ethyl acetate (15 ml), and 10% palladiumcarbon (346 mg) was added to the resulting mixture followed by stirringfor 12 hours at room temperature under hydrogen atmosphere. The catalystwas removed by filtration and the solvent was distilled off underreduced pressure. The residue was dissolved again in ethyl acetate (15ml), and palladium carbon (340 mg) was added to the resulting mixturefollowed by stirring for 20 hours at room temperature under hydrogenatmosphere. The catalyst was removed by filtration and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel flash column chromatography (eluent: hexane/ethyl acetate=5/1) togive ethyl10-[(3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate(1.05 g, Yield 91%).

¹H-NMR (270 MHz, CDCl₃): d 7.25 (d, J=9 Hz, 2H, Ar—H), 6.92 (d, J=9 Hz,1H, Ar—H), 6.90 (d, J=9 Hz, 2H, Ar—H), 6.71 (d, J=2 Hz, 1H, Ar—H), 6.56(dd, J=9, 2 Hz, 1H, Ar—H), 4.12 (q, J=6 Hz, 2H, CO₂CH ₂CH₃), 3.82 (s,3H, OCH₃), 3.77 (s, 3H, OCH₃), 3.48 (d, J=12 Hz, 1H, C2-H), 3.23 (d,J=12 Hz, 1H, C2-H), 2.79 (m, 1H, C4-H), 2.28 (m, 1H, CHCO₂Et), 2.10-1.95(m, 2H, CH ₂CF₂), 1.70-0.90 (m, 31H, C3-CH ₂CH₃, CO₂CH₂CH ₃ andalkyl-H), 0.48 (t, 3H, J=7 Hz, 2H, C3-CH₂CH ₃).

A solution of boron tribromide in dichloromethane (1.0 M, 8.82 ml, 8.82mmol) was added dropwise to a solution of ethyl10-[(3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate(1.05 g, 1.47 mmol) in dichloromethane (15 ml) at −78° C. under argonatmosphere. The reaction mixture was warmed with stirring up to 10° C.over 3 hours. Water was added to the reaction mixture, which was thenextracted with ethyl acetate. The organic layer was washed with waterand saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the resultingresidue was dissolved in ethanol (5 ml) and mixed with concentratedsulfuric acid (1 drop), followed by heating under reflux for 12 hours.Water was added to the reaction mixture, which was then extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gel flashcolumn chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate(550 mg, Yield 55%).

¹H-NMR (270 MHz, CDCl₃): d 7.22 (d, J=8 Hz, 2H, Ar—H), 6.85 (d, J=8 Hz,1H, Ar—H), 6.84 (d, J=8 Hz, 2H, Ar—H), 6.66 (d, J=2 Hz, 1H, Ar—H), 6.47(dd, J=8, 2 Hz, 1H, Ar—H), 6.21 (br s, 1H, OH), 5.30 (br s, 1H, OH),4.17 (q, J=7 Hz, 2H, CO₂CH ₂CH₃), 3.46 (d, J=12 Hz, 1H, C2-H), 3.08 (d,J=12 Hz, 1H, C2-H), 2.71 (m, 1H, C4-H), 2.34 (m, 1H, CHCO₂Et), 2.10-1.90(m, 2H, CH ₂CF₂), 1.85-0.80 (m, 31H, C3-CH ₂CH₃, CO₂CH₂CH ₃ andalkyl-H), 0.50 (t, 3H, J=7 Hz, 2H, C3-CH₂CH ₃).

A solution of sodium hydroxide (325 mg) in water (4 ml) was added to asolution of ethyl10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate(558 mg, 0.81 mmol) in ethanol (8 ml). The reaction mixture was heatedunder reflux for 12 hours. Dilute hydrochloric acid was added to thereaction mixture, which was then extracted with ethyl acetate. Theorganic layer was washed with water and saturated aqueous sodiumchloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gel flashcolumn chromatography (eluent: hexane/ethyl acetate=2/1) to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluoro-octyl)decanoicacid (480 mg, Yield 89%).

¹H-NMR (270 MHz, CDCl₃): d 7.17 (d, J=9 Hz, 2H, Ar—H), 6.86 (d, J=8 Hz,1H, Ar—H), 6.83 (d, J=9 Hz, 2H, Ar—H), 6.66 (d, J=2 Hz, 1H, Ar—H), 6.48(dd, J=8, 2 Hz, 1H, Ar—H), 3.46 (d, J=12 Hz, 1H, C2-H), 3.08 (d, J=12Hz, 1H, C2-H), 2.72 (br s, 1H, C4-H), 2.34 (m, 1H, CHCO₂Et), 2.10-1.85(m, 2H, CH ₂CF₂), 1.70-0.90 (m, 28H, C3-CH ₂CH₃and alkyl-H), 0.49 (t,3H, J=7 Hz, 2H, C3-CH₂CH ₃).

Example 14 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)-decanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared in Example 11, thesame procedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.16 (d, 2H, J=8.7 Hz), 6.89-6.81 (m, 3H),6.66 (s, 1H), 6.47 (m, 1H), 3.47 (d, 1H, J=11.9 Hz), 3.08 (d, 1H, J=11.9Hz), 2.82 (m, 1H), 2.36 (m, 1H), 2.10-1.90 (m, 2H), 1.70-0.95 (m, 26H),0.50 (t, 3H, J=7.3 Hz).

Example 15 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)-decanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared in Example 9, thesame procedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.18 (d, 2H, J=8.7 Hz), 6.88-6.81 (m, 3H),6.65 (d, 1H, J=2.3 Hz), 6.47 (dd, 1H, J=8.3 Hz, J=2.6 Hz), 3.46 (d, 1H,J=11.7 Hz), 3.09 (d, 1H, J=11.7 Hz), 2.74 (m, 1H), 2.40 (m, 1H),2.10-1.93 (m, 4H), 1.47-0.98 (m, 22H), 0.50 (t, 3H, J=7.4 Hz).

Example 16 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-decanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared in Example 10, thesame procedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.15 (d, 2H, J=9.0 Hz), 6.92-6.80 (m, 3H),6.64 (d, 1H, J=2.6 Hz), 6.47 (dd, 1H, J₁=8.3 Hz, J₂=2.6 Hz), 3.44 (d,1H, J=11.7 Hz), 3.07 (d, 1H, J=11.7 Hz), 2.71 (bs, 1H), 2.37 (m, 1H),2.01-1.98 (m, 2H), 1.75-1.49 (m, 6H), 1.40-1.38 (m, 2H), 1.26-0.93 (m,14H), 0.47 (t, 3H, J=7.2 Hz). Mass (ESI): 617 (M+1).

Example 17 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate prepared in Example 8, thesame procedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoicacid.

¹H-NMR (270 MHz, CDCl₃) d: 7.16 (d, J=8.6 Hz, 2H), 6.83 (t, J=9.6 Hz,3H), 6.64 (d, J=2.3 Hz, 2H), 6.46 (dd, J=2.3, 8.0 Hz, 1H), 3.43 (d,J=11.9 Hz, 1H), 3.07 (d, J=11.9 Hz, 1H), 2.72 (s, 1H), 2.52-2.35 (m,1H), 2.10-0.90 (m, 24H), 0.47 (t, J=7.6 Hz, 3H).

Example 18 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate prepared in Example 7, thesame procedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoicacid.

¹H-NMR (270 MHz, CD₃OD): d 7.18 (d, J=8 Hz, 2H, Ar—H), 6.85 (d, J=8 Hz,1H, Ar—H), 6.79 (d, J=8 Hz, 2H, Ar—H), 6.56 (d, J=2 Hz, 1H, Ar—H), 6.43(dd, J=8, 2 Hz, 1H, Ar—H), 3.43 (d, J=12 Hz, 1H, C2-H), 3.10 (d, J=12Hz, 1H, C2-H), 2.76 (br s, 1H, C4-H), 2.38-2.21 (m, 1H, CHCO₂H),2.29-1.98 (m, 2H, CH ₂CF₂), 1.69-0.90 (m, 28H, C3-CH ₂CH₃ and alkyl-H),0.48 (t, 3H, J=7 Hz, C3-CH₂CH ₃).

Example 19 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared in Example 5, thesame procedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.15 (d, 2H, J=9.9 Hz), 6.89-6.80 (m, 3H),6.55 (d, 1H, J=2.7 Hz), 6.40 (dd, 1H, J₁=8.3 Hz , J₂=2.7 Hz), 3.45 (d,1H, J=11.9 Hz), 3.09 (d , 1H, J=11.9 Hz), 2.72 (m, 1H), 2.32 (m, 1H),2.03-2.01 (m, 2H), 1.70-0.90 (m, 26H), 0.50 (t, 3H, J=7.4 Hz). Mass(ESI): 645 (M+1).

Example 20 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 13 and the ethyl2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared in Example 6, thesame procedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): d 7.18 (d, J=9 Hz, 2H, Ar—H), 6.87 (d, J=8 Hz,1H, Ar—H), 6.84 (d, J=9 Hz, 2H, Ar—H), 6.66 (d, J=2 Hz, 1H, Ar—H), 6.49(dd, J=8, 2 Hz, 1H, Ar—H), 3.46 (d, J=12 Hz, 1H, C2-H), 3.09 (d, J=12Hz, 1H, C2-H), 2.74 (m, 1H, C4-H), 2.42 (m, 1H, CHCO₂ H), 2.12-1.94 (m,2H, CH ₂CF₂), 1.78-1.00 (m, 24H, C3-CH ₂CH₃ and alkyl-H), 0.49 (t, 3H,J=7 Hz, C3-CH₂CH ₃).

Example 21 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)-undecanoicAcid

A suspension of 2-hydroxy-4-methoxybenzaldehyde (6.10 g),4-methoxyphenylacetylchloride (11.1 g) and potassium carbonate (20 g) inacetone (400 ml) was heated under reflux for 2 hours. The reactionmixture was evaporated to remove the solvent, followed by addition ofwater. The resulting precipitates were collected by filtration and driedunder reduced pressure to give7-methoxy-3-(4-methoxyphenyl)-chromen-2-one (10.1 g, Yield 89%).

¹H-NMR (270 MHz, CDCl₃): d 7.71 (s, 1H, Ar—H), 7.65 (d, 2H, J=8.9 Hz,Ar—H), 7.42 (d, 1H, J=8.9 Hz, Ar—H), 6.97 (d, 2H, J=8.9 Hz, Ar—H),6.8-6.9 (m, 2H, Ar—H), 3.88 (s, 3H, MeO), 3.85 (s, 3H, MeO).

7-Methoxy-3-(4-methoxyphenyl)-chromen-2-one (21.8 g) was mixed withpyridine hydrochloride (80 g) and stirred for 1 hour at a temperature of190° C. to 200° C. Water was added to the reaction mixture and theresulting precipitates were collected by filtration and dried underreduced pressure to give 7-hydroxy-3-(4-hydroxyphenyl)-chromen-2-one(19.6 g, Yield 100%). Diisopropylethylamine (35 ml)in dimethylformamide(70 ml) and methoxymethyl chloride (10.4 ml) were added to a solution of7-hydroxy-3-(4-hydroxyphenyl)-chromen-2-one thus prepared (8.74 g)followed by stirring for 2 hours at 80° C. After cooling, water wasadded to the reaction mixture and the resulting precipitates werecollected by filtration and dried under reduced pressure to give7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chromen-2-one (8.67 g, Yield74%).

¹H-NMR (270 MHz, CDCl₃): d 7.71 (s, 1H, Ar—H), 7.64 (d, 2H, J=8.9 Hz,Ar—H), 7.43 (d, 1H, J=8.3 Hz, Ar—H), 7.10 (d, 2H, J=8.9 Hz, Ar—H),6.9-7.1 (m, 2H, Ar—H), 5.24 (s, 2H, OCH ₂OMe), 5.22 (s, 2H, OCH ₂OMe),3.50 (s, 3H, MeO), 3.49 (s, 3H, MeO).

TBAF·n-H₂O (6 g) was azeotroped with toluene and ethanol (20 ml each)under reduced pressure to remove water and then concentrated twice withtoluene (20 ml) under reduced pressure. The resulting light-yellow oilwas dried using a vacuum pump to prepare anhydrous TBAF. A solution ofthis anhydrous TBAF in dry dimethylformamide (80 ml) was added to asuspension of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chromen-2-one(14.8 g) in dry dimethylformamide (80 ml). To this suspension, asolution of HMPA (vacuum distilled while drying over calcium hydride,27.1 ml) and allyltrimethylsilane (24.7 ml) in dry dimethylformamide (80ml) was added dropwise at room temperature over 15 minutes. Theresulting red reaction mixture was stirred for 2 hours at roomtemperature and quenched with 1N hydrochloric acid (100 ml) in methanol(200 ml) on ice. The reaction mixture was extracted three times withethyl acetate. The combined organic layers were washed three times withwater and dried over magnesium sulfate. After concentration underreduced pressure, the resulting crude product was purified by silica gelcolumn chromatography (Wakogel C-200, eluent: hexane/ethylacetate=10/1→9/1) to give7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one(14.1 g, Yield 85.0%) as a yellow oil.

¹H-NMR (270 MHz, CDCl₃): d 7.23 (d, 1H, J=8.6 Hz, Ar—H), 7.0-7.1 (m, 3H,Ar—H), 6.90 (d, 1H, 8.6 Hz, Ar—H), 6.7-6.9 (m, 2H, Ar—H), 5.5-5.9 (m,1H, vinyl-H), 5.10, 5.15, 5.18 (each s, 4H, OCH₂OMe), 4.8-5.2 (m, 2H,vinyl-H), 4.14 (d, 0.4H, J=5.6 Hz, C3-H), 4.03 (d, 0.6H, J=3.3 Hz,C3-H), 3.50, 3.48, 3.43 (each s, 6H, OCH₃), 3.19 (td, 0.6H, J=6.9, 3.3Hz, C4-H), 3.05-3.15 (m, 0.4H, C4-H), 2.1-2.5 (m, 2H, allylic-H).

A 1M solution of lithium hexamethyl-disilazide in tetrahydrofuran (86.2ml) was added dropwise to a solution of7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one(16.57 g) in dry tetrahydrofuran (86.2 ml) at −78° C. over 30 minutesunder nitrogen atmosphere, followed by stirring for 20 minutes at 0° C.After the reaction mixture was cooled to −78° C., ethyl triflate (21.6ml) was added dropwise thereto over 20 minutes and the resulting mixturewas warmed to −30° C. over 3 hours, followed by addition of pyridine(13.9 ml). This mixture was stirred for 15 minutes at −30° C., cooled to−78° C., and further mixed with saturated aqueous ammonium chloride (100ml) and water (50 ml). After extraction with ethyl acetate, the organiclayer was washed with 0.05 N aqueous hydrochloric acid and saturatedaqueous sodium chloride, and then dried over anhydrous sodium sulfate.After concentration under reduced pressure, the resulting oil waspurified by flash column chromatography (silica gel: Merck Kieselgel 60,eluent: hexane/ethyl acetate=5/1→4/1) to give(3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one(14.98 g, Yield 84.3%) as a white solid.

¹H-NMR (270 MHz, CDCl₃): d 7.54 (d, 2H, J=8.9 Hz, Ar—H), 7.05 (d, 2H,J=8.9 Hz, Ar—H), 7.00 (d, 1H, J=8.9 Hz, Ar—H), 6.7-6.8 (m, 2H, Ar—H),5.4-5.6 (m, 1H, vinyl-H), 5.17, 5.20 (each s, 4H, OCH₂OMe), 4.89 (d, 1H,J=10.2 Hz, vinyl-H), 4.73 (dd, 1H, J=17.2, 1.7 Hz, vinyl-H), 3.502,3.498 (each s, 6H, OCH₃), 2.91 (dd, 1H, J=9.9, 3.6 Hz, C4-H), 1.8-2.2(m, 4H, allylic-H and CH ₂Me), 0.70 (t, 3H, J=7.3 Hz, CH₂ CH ₃).

A solution of(3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one(9.4 g) in dry tetrahydrofuran (50 ml) was added dropwise to an ice-coldsuspension of lithium aluminum hydride (2.2 g) in dry tetrahydrofuran(50 ml) over 25 minutes under nitrogen atmosphere, and the reactionmixture was then stirred on ice for 1 hour and 15 minutes. Ethyl acetate(30 ml) and saturated aqueous ammonium chloride (30 ml) were added tostop the reaction, followed by stirring for 1 hour at room temperature.The reaction mixture was filtered through cellite and the resultingfiltrate was extracted twice with ethyl acetate. The combined organiclayers were washed with saturated aqueous ammonium chloride, dried overmagnesium sulfate, and then concentrated under reduced pressure to give(2RS,3RS)-2-ethyl-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxyphenyl)-5-hexenol(9.5 g, quantitative) as a crude product, which was then used for thesubsequent reaction without further purification.

¹H-NMR (270 MHz, CDCl₃): d 7.4-7.5 (bs, 1H, Ar—OH), 6.94 (d, 2H, J=9.2Hz, Ar—H), 6.86 (d, 2H, J=9.2 Hz, Ar—H), 6.57 (d, 1H, J=2.6 Hz, Ar—H),6.31 (dd, 1H, J=8.9, 2.6 Hz, Ar—H), 5.91 (d, 1H, J=8.9 Hz, Ar—H),5.3-5.5 (m, 1H, vinyl-H), 5.17, 5.20 (each d, 2H, J=6.9 Hz, OCH₂OMe),5.10, 5.13 (each d, 2H, J=6.9 Hz, OCH₂OMe), 4.84 (dd, 1H, J=17.2, 2.0Hz, vinyl-H), 4.75 (dd, 1H, J=9.9, 2.0 Hz, vinyl-H), 3.7-3.9 (m, 1H,C1-H), 3.6-3.7 (m, 1H, C1-H), 3.51, 3.48 (each s, 6H, OCH₃), 3.31 (dd,1H, J=11.5, 3.3 Hz, C3-H), 2.7-2.9 (bs, 1H, C1-OH), 2.6-2.7 (m, 1H,C4-H), 2.3-2.5 (m, 1H, CH ₂Me), 1.9-2.1 (m, 2H, C4-H and CH ₂Me), 0.79(t, 3H, J=7.3 Hz, CH₂ CH ₃).

A 40% solution of diethyl azodicarboxylate in toluene (21.9 ml) wasadded dropwise to an ice-cold solution of(2RS,3RS)-2-ethyl-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxy-phenyl)-5-hexenol(9.5 g) and triphenylphosphine (15.0 g) in dry 1,4-dioxane (150 ml) over25 minutes under nitrogen atmosphere. The reaction mixture was stirredfor 10 minutes on ice and for 30 minutes at room temperature. Underice-cooling, water was added to the reaction mixture, which was thenextracted twice with ethyl acetate. The combined organic layers weredried over magnesium sulfate and then concentrated to give a crudeproduct, which was then purified by flash column chromatography (silicagel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=50/1→20/1→10/1) togive(3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman(8.4 g, Yield 92.6%) as a white solid.

¹H-NMR (270 MHz, CDCl₃): d 7.08, 7.03 (each d, 4H, J=8.9 Hz, Ar—H), 6.94(d, 1H, J=7.9 Hz, Ar—H), 6.5-6.6 (m, 2H, Ar—H), 5.5-5.7 (m, 1H,vinyl-H), 5.19, 5.14 (each s, 4H, OCH₂OMe), 4.85 (d, 1H, J=10.2 Hz,vinyl-H), 4.69 (dd, 1H, J=16.8, 1.7 Hz, vinyl-H), 4.49 (dd, 1H, J=10.6,2.0 Hz, C2-H), 4.36 (d, 1H, J=10.6 Hz, C2-H), 3.51, 3.49 (each s, 6H,OCH₃), 2.7-2.9 (m, 1H, C4-H), 2.0-2.1 (m, 1H, allylic-H), 1.7-1.9 (m,2H, allylic-H and CH ₂Me), 1.4-1.6 (m, 1H, CH ₂Me), 0.60 (t, 3H, J=7.3Hz, CH₂ CH ₃).

(3RS,4RS)-3-Ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman(995 mg), the ethyl 2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate preparedin Example 8 (2.0 g) and benzylidene bis(tricyclohexylphosphine)-dichlororuthenium (102 mg) were dissolved indichloromethane (25 ml) and heated under reflux for 7 hours. Thereaction mixture was concentrated and purified by flash columnchromatography (silica gel: Merck Kieselgel 60, eluent:hexane/ethylacetate=20/1→10/1) to give the desired olefin (1.05 g, Yield 55%) as amixture of cis- and trans-forms. A solution of this mixture in ethylacetate (50 ml) was stirred-with 10% Pd-C (210 mg) for 4 days underhydrogen atmosphere. The reaction mixture was filtered and evaporatedunder reduced pressure to remove the solvent, followed by purificationvia flash column chromatography (silica gel: Merck Kieselgel 60,eluent:hexane/ethyl acetate=10/1) to give ethyl11-[(3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoate(1.02 g).

¹H-NMR (270 MHz, CDCl₃): d 6.9-7.2 (m, 5H, Ar—H), 6.5-6.6 (m, 2H, Ar—H),5.18 (s, 2H, OCH ₂OMe), 5.14 (s, 2H, OCH ₂OMe), 4.47 (dd, 1H, J=1.7,11.0 Hz, C2-H), 4.35 (d, 1H, J=11.0 Hz, C2-H), 4.12 (q, 2H, J=7.2 Hz,OCH ₂CH₃) 3.50 (s, 3H, OMe), 3.49 (s, 3H, OMe), 2.6-2.7 (m, 1H, C4-H),2.2-2.4 (m, 1H), 1.9-2.1 (m, 2H), 1.24 (t, 3H, J=7.1 Hz,OCH₂ CH ₃)0.9-1.8 (m, 30H), 0.58 (t, 3H, J=7.2 Hz, CH₂ CH ₃).

7N hydrochloric acid (12 ml) was added to a solution of ethyl11-[(3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoate(1.02 g) in ethanol (30 ml) followed by stirring for 1 day at roomtemperature and concentrated hydrochloric acid (1 ml) was further addedto it followed by stirring for 1 hour at 25° C. The reaction mixture wasneutralized by addition of saturated aqueous sodium bicarbonate,evaporated under reduced pressure to remove the solvent, and thenextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure to remove thesolvent, followed by purification via flash column chromatography(silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=10/1) togive a MOM-deprotected product (780 mg). The MOM-deprotected productthus prepared (780 mg) was dissolved in ethanol (25 ml). Aqueous sodiumhydroxide (sodium hydroxide 364 mg/water 6.5 ml) was added to thissolution followed by stirring for 3 hours at 80° C. The reaction mixturewas cooled on ice, acidified by addition of concentrated hydrochloricacid, and then extracted with ethyl acetate. The organic layer waswashed with water and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, and evaporated under reduced pressure toremove the solvent, followed by purification via flash columnchromatography (silica gel: Wako C-200, eluent:hexane/ethylacetate/dichloromethane=5/1/1→3/1/1) to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)-undecanoicacid (612 mg).

¹H-NMR (270 MHz, CD₃OD): d 7.02 (d, 2H, J=8.5 Hz, Ar—H), 6.84 (d, 1H,J=8.2 Hz, Ar—H), 6.79 (d, 2H, J=8.5 Hz, Ar—H), 6.30 (dd, 1H, J=2.5, 8.2Hz, Ar—H), 6.24 (d, 1H, J=2.5 Hz, Ar—H), 4.44 (dd, 1H, J=1.6, 11.0 Hz,C2-H), 4.31 (d, 1H, J=11.0 Hz, C2-H), 2.5-2.7 (m, 1H, C4-H), 2.2-2.4 (m,1H), 2.0-2.2 (m, 2H), 0.9-1.8 (m, 30H), 0.57 (t, 3H, J=7.4 Hz, CH₂ CH₃).

Example 22 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate prepared in Example 7, thesame procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 6.98 (d, 2H, J=8.5 Hz), 6.88-6.80 (m, 3H),6.36-6.34 (m, 2H), 4.37 (m, 2H), 2.60 (m, 1H), 2.40 (m, 1H), 2.10-1.85(m, 2H), 1.80-0.90 (m, 28H), 0.56 (t, 3H, J=7.3 Hz).

Example 23 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared in Example 5, thesame procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoicacid.

¹H-NMR (270 MHz, CD₃OD): d 7.02 (d, J=9 Hz, 2H, Ar—H), 6.84 (d, J=8, 2Hz, 1H, Ar—H), 6.78 (d, J=9 Hz, 2H, Ar—H), 6.29 (dd, J=8, 2 Hz, 1H,Ar—H), 6.22 (d, J=2 Hz, 1H, Ar—H), 4.43 (dd, J=11, 2 Hz, 1H, C2-H), 4.30(d, J=11 Hz, 1H, C2-H), 2.55-2.65 (m, 1H, C4-H), 2.20-2.40 (m, 1H,CHCO₂Et), 1.95-2.20 (m, 2H, CH ₂CF₂), 0.95-1.80 (m, 26H, C3-CH ₂CH₃ andalkyl-H), 0.56 (t, 3H, J=7 Hz, C3-CH₂CH ₃).

Example 24 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared in Example 6, thesame procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.00 (d, 2H, J=8.6 Hz), 6.88 (d, 1H, J=9.0Hz), 6.85 (d, 2H, J=8.7 Hz), 6.37-6.32 (m, 2H), 4.45 (dd, 1H, J₁=10.7Hz, J₂=1.5 Hz), 4.35 (d, 1H, J=10.7 Hz), 2.60 (m, 1H), 2.41 (m, 1H),2.01-1.92 (m, 2H), 1.78-1.39 (m, 8H), 1.35-0.98 (m, 16H), 0.58 (t, 3H).Mass (ESI): 615 (M+1).

Example 25 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate prepared in Example 12, thesame procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.02-6.96 (m, 2H), 6.88-6.80 (m, 3H),6.38-6.34 (m, 2H), 4.46-4.32 (m, 2H), 2.60 (m, 1H), 2.37 (m, 1H),2.10-1.90 (m, 2H), 1.76-1.68 (m, 2H), 1.55-1.00 (m, 26H), 0.55 (t, 3H,J=7.5 Hz). Mass (ESI): 643 (M+1).

Example 26 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)-decanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared in Example 11, thesame procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 6.98 (d, 2H), 6.92-6.78 (m, 3H), 6.39-6.29(m, 2H), 4.45 (d, 1H), 4.35 (d, 1H), 2.61 (bs, 1H), 2.38 (m, 1H),2.10-1.88 (m, 2H), 1.80-1.31 (m, 9H), 1.31-0.96 (m, 17H), 0.56 (t, 3H).

Example 27 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared in Example 9, thesame procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 6.98 (d, 2H), 6.90-6.77 (m, 3H), 6.39-6.29(m, 2H), 4.47 (d, 1H), 4.36 (d, 1H), 2.59 (bs, 1H), 2.38 (m, 1H),2.12-1.89 (m, 2H), 1.80-1.35 (m, 9H), 1.35-0.95 (m, 15H), 0.55 (t, 3H).

Example 28 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-decanoicAcid

Starting with the allyl compound prepared in Example 21 and the ethyl2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared in Example 10, thesame procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.00 (d, 2H), 6.89-6.84 (m, 3H), 6.37-6.34(m, 2H), 4.45 (d, 1H), 4.35 (d, 1H), 2.61 (bs, 1H), 2.40 (m, 1H),2.15-1.95 (m, 2H), 1.80-1.35 (m, 9H), 1.35-0.95 (m, 13H), 0.60 (t, 3H).Mass (ESI): 601 (M+1).

Example 29 Synthesis of10-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-decanoicAcid

Allyl bromide (5.7 ml, 66.56 mmol) was added dropwise to a solution of7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.64 mmol) indimethyl sulfoxide (34 ml). To this mixture, a solution of potassiumtert-butoxide (5.22 g, 46.55 mmol) in dimethyl sulfoxide (70 ml) wasslowly added dropwise at 10° C., followed by stirring for 2 hours at 10°C. and for 15 hours at room temperature. Water was added to the reactionmixture, which was then extracted three times with ethyl acetate. Thecombined organic layers were washed with water and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent:ethyl acetate/hexane=1/9) to give7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.78 g,Yield 79%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.16 (d, 1H, J=8.9 Hz), 7.15 (d, 2H, J=8.9Hz), 6.82 (d, 2H, J=8.9 Hz), 6.67 (dd, 1H), 6.53 (d, 1H), 5.62 (m, 1H),5.06 (d, 2H, J=12.5 Hz), 3.82 (s, 6H), 3.59 (d, 1H, J=14.2 Hz,), 3.36(d, 1H, J=14.2 Hz), 2.80-2.70 (m, 2H).

10% Pd/C (580 mg) was added to a solution of7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.75 g,5.14 mmol) in ethyl acetate (20 ml) followed by stirring for 15 hours atroom temperature under a hydrogen stream. Pd/C was removed by filtrationthrough cellite and the resulting filtrate was concentrated underreduced pressure to give7-methoxy-3-(4-methoxyphenyl)-3-propylthiochroman-4-one (1.7 g, Yield96%).

¹H-NMR (270 MHz, CDCl₃): δ 8.17 (d, 1H, J=8.9 Hz), 7.17 (d, 2H, J=8.6Hz), 6.84 (d, 2H, J=8.9 Hz), 6.69 (dd, 1H), 6.56 (d, 1H, J=2.6 Hz), 3.8(s, 6H), 3.62 (d, 1H, J=14.0 Hz), 3.45 (d, 1H, J=14.0 Hz), 1.97 (t, 2H),1.30-1.21 (m, 2H), 0.89 (t, 3H).

A solution of 7-methoxy-3-(4-methoxyphenyl)-3-propylthiochroman-4-one(1.7 g, 4.96 mmol) in anhydrous tetrahydrofuran (30 ml) was cooled to−78° C. Lithium aluminum hydride (94.2 mg, 2.48 mmol) was added to thissolution, followed by stirring for 12 hours at room temperature.Saturated aqueous ammonium chloride (100 ml) was added to the reactionmixture, which was then extracted twice with ethyl acetate (100 ml). Thecombined organic layers were washed with water and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, zinc iodide (1.9 g, 5.95 mmol) andallyltrimethylsilane (1.57 ml, 5.95 mmol) were added dropwise to asolution of the residue in 1,2-dichloroethane (50 ml) at 0° C., followedby stirring for 12 hours at room temperature. Water was added to thereaction mixture, which was then extracted twice with dichloromethane.The combined organic layers were washed with water and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent:ethyl acetate/hexane=1/90) to give(3RS,4RS)-7-methoxy-3-(4-methoxyphenyl)-4-(2-propenyl)-3-propylthiochroman(1.32 g, Yield 72%).

¹H-NMR (300 MHz, CDCl₃): δ 7.25 (d, 2H, J=6.9 Hz), 7.05-6.86 (m, 3H),6.71 (d, 1H, J=2.3 Hz), 6.56 (dd, 1H), 5.54 (m, 1H), 4.84 (d, 1H), 4.65(d, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 3.49 (d, 1H), 3.12 (d, 1H), 2.88(m, 1H), 1.88 (m, 2H), 1.68 (m, 1H), 1.36 (m, 1H), 1.09 (m, 1H),0.95-0.57 (m, 4H).

Starting with the allyl compound prepared in Step 3 and the ethyl2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared in Example 10, thesame procedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.18 (d, 2H, J=8.7 Hz), 6.90-6.75 (m, 3H),6.66 (d, 1H, J=2.8 Hz), 6.49 (dd, 1H, J₁=8.2 Hz J₂=2.6 Hz), 3.48 (d, 1H,J=12.01 Hz), 3.08 (d, 1H, J=12.0 Hz), 2.70 (m, 1H), 2.40 (m, 1H),2.10-1.90 (m, 2H), 1.80-1.40 (m, 6H), 1.40-0.90 (m, 17H), 0.80-0.55 (m,4H). Mass (ESI): 631 (M+1).

Example 30 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicAcid

Starting with the ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared from diethylmalonate, 8-bromo-1-octene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexaneas in Example 5 and the allyl compound prepared in Example 13, the sameprocedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid.

¹H-NMR (270 MHz, CDCl₃): d 7.16 (d, J=8.6 Hz, 2H), 6.83 (t, J=9.6 Hz,3H), 6.64 (d, J=2.3 Hz, 1H), 6.46 (dd, J=2.3, 8.0 Hz, 1H), 3.43 (d,J=11.9 Hz, 1H), 3.07 (d, J=11.9 Hz, 1H), 2.72 (s, 1H), 2.52-2.35 (m,1H), 2.10-0.90 (m, 24H), 0.47 (t, J=7.6 Hz, 3H).

Example 31 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicAcid

Starting with the ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared from diethylmalonate, 7-iodo-1-heptene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexaneas in Example 9 and the allyl compound prepared in Example 13, the sameprocedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): d 7.17 (d, J=9 Hz, 2H, Ar—H), 6.86 (d, J=8 Hz,1H, Ar—H), 6.83 (d, J=9 Hz, 2H, Ar—H), 6.66 (d, J=2 Hz, 1H, Ar—H), 6.48(dd, J=8 Hz, 2 Hz, 1H, Ar—H), 3.46 (d, J=12 Hz, 1H, C2-H), 3.08 (d, J=12Hz, 1H, C2-H), 2.72 (br s, 1H, C4-H), 2.45 (m, 1H, CHCO₂H), 2.2-2.0 (m,2H, CH ₂CF₂), 2.0-0.9 (m, 20H, C3-CH ₂CH₃ and alkyl-H), 0.49 (t, 3H, J=7Hz, 2H, C3-CH₂CH ₃).

Example 32 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-undecanoicAcid

Starting with the ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared from diethylmalonate, 8-bromo-1-octene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexaneas in Example 5 and the allyl compound prepared in Example 21, the sameprocedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.00 (d, 2H, J=9.6 Hz), 6.8 (d, 1H), 6.70 (d,1H, J=8.6 Hz), 6.38-6.34 (m, 2H), 4.45 (d, 1H, J=10.7 Hz), 4.30 (d, 1H,J=10.7 Hz), 2.62 (m, 1H), 2.45 (m, 1H), 2.20-0.95 (m, 24H), 0.54 (t,3H). Mass (ESI): 700 (M+1).

Example 33 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-decanoicAcid

Starting with the ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared from diethylmalonate, 7-iodo-1-heptene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexaneas in Example 9 and the allyl compound prepared in Example 21, the sameprocedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.02 (d, 2H, J=8.7 Hz), 6.87 (d, 1H, J=7.5Hz), 6.84 (d, 2H, J=8.7 Hz), 6.40-6.30 (m, 2H), 4.45 (d, 1H, J=10.6 Hz),4.35 (d, 1H, J=10.6 Hz), 2.61 (bs, 1H), 2.36 (m, 1H), 2.19-0.97 (m,22H), 0.59 (t, 3H). Mass (ESI): 687 (M+1).

Example 34 Synthesis of10-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicAcid

Starting with the allyl compound prepared in Example 21 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately,the same procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR (270 MHz, CDCl₃): δ 7.01 (d, J=9 Hz, 2H, Ar—H), 6.90-6.82 (m, 3H,Ar—H), 6.38-6.35 (m, 2H, Ar—H), 4.45 (d, J=11 Hz, 1H), 4.34 (d, J=11 Hz,1H), 2.60 (m, 1H), 2.41-2.36 (m, 1H), 2.10-1.05 (m, 24H), 0.58 (t, J=7Hz, 3H).

Example 35 Synthesis of11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicAcid

Starting with the allyl compound prepared in Example 21 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared separately,the same procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid.

¹H-NMR (270 MHz, CDCl₃): δ 6.99 (d, J=9 Hz, 2H, Ar—H), 6.89-6.80 (m, 3H,Ar—H), 6.36-6.33 (m, 2H, Ar—H), 4.44 (d, J=11 Hz, 1H), 4.33 (d, J=11 Hz,1H),2.59 (m, 1H), 2.39-2.34 (m, 1H), 2.16-1.05 (m, 26H), 0.56 (t, J=7Hz, 3H).

Example 36 Synthesis of10-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)-decanoicAcid

Starting with the allyl compound prepared in Example 29 and ethyl2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared separately, the sameprocedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.18 (d, J=8.7 Hz, 2H, Ar—H), 6.80-6.87 (m,3H, Ar—H), 6.66 (d, J=2.5 Hz, 1H, Ar—H), 6.49 (dd, J=8.2, 2.5 Hz, 1H,Ar—H), 3.46 (d, J=12.0 Hz, 1H, SCH₂), 3.08 (d, J=12.0 Hz, 1H, SCH₂),2.70-2.72 (m, 1H, Ar—CH), 2.37-2.39 (m, 1H, CHCO₂H), 1.96-2.13 (m, 2H,CH ₂CF₂), 0.62-1.64 (m, 29H, alkyl-H) Mass (ESI): 645 (M+1).

Example 37 Synthesis of10-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicAcid

Starting with the allyl compound prepared in Example 29 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately,the same procedure as shown in Example 13 was repeated to give10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.18 (d, J=8.7 Hz, 2H, Ar—H), 6.87 (d, J=8.1Hz, 1H, Ar—H), 6.83 (d, J=8.7 Hz, 2H, Ar—H), 6.67 (d, J=2.5 Hz, 1H,Ar—H), 6.49 (dd, J=8.1, 2.5 Hz, 1H, Ar—H), 3.46 (d, J=11.8 Hz, 1H,SCH₂), 3.09 (d, J=11.8 Hz, 1H, SCH₂), 2.66-2.75 (m, 1H, Ar—CH),2.33-2.47 (m, 1H, CHCO₂H), 1.96-2.21 (m, 2H, CH ₂CF₂), 0.59-1.93 (m,25H, alkyl-H) Mass (ESI): 717 (M+1).

Example 38 Synthesis of11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5,-pentafluoropentyl)-undecanoicAcid

Starting with the allyl compound prepared in Example 29 and ethyl2-(4,4,5,5,5,-pentafluoropentyl)-9-decenoate prepared separately, thesame procedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5,-pentafluoropentyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.18 (d, J=8.7 Hz, 2H, Ar—H), 6.87 (d, J=8.1Hz, 1H, Ar—H), 6.83 (d, J=8.7 Hz, 2H, Ar—H), 6.67 (d, J=2.5 Hz, 1H,Ar—H), 6.49 (dd, J=8.1, 2.5 Hz, 1H, Ar—H), 3.47 (d, J=11.8 Hz, 1H,SCH₂), 3.09 (d, J=11.8 Hz, 1H, SCH₂), 2.68-2.76 (m, 1H, Ar—CH),2.34-2.47 (m, 1H, CHCO₂H), 1.93-2.16 (m, 2H, CH ₂CF₂), 0.59-1.85 (m,29H, alkyl-H) Mass (ESI): 645 (M+1).

Example 39 Synthesis of11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicAcid

Starting with the allyl compound prepared in Example 29 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared separately,the same procedure as shown in Example 13 was repeated to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.18 (d, J=8.7 Hz, 2H, Ar—H), 6.87 (d, J=8.3Hz, 1H, Ar—H), 6.83 (d, J=8.7 Hz, 2H, Ar—H), 6.67 (d, J=2.3 Hz, 1H,Ar—H), 6.49 (dd, J=8.3, 2.2 Hz, 1H, Ar—H), 3.46 (d, J=12.1 Hz, 1H,SCH₂), 3.09 (d, J=11.8 Hz, 1H, SCH₂), 2.68-2.75 (m, 1H, Ar—CH),2.40-2.50 (m, 1H, CHCO₂H), 2.00-2.20 (m, 2H, CH ₂CF₂), 0.60-1.95 (m,27H, alkyl-H). Mass (ESI): 731 (M+1).

Example 40 Synthesis of10-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared separately, the sameprocedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.01 (d, J=8.7 Hz, 2H, Ar—H), 6.81-6.90 (m,3H, Ar—H), 6.36-6.38 (m, 2H, Ar—H), 4.45 (d, J=10.5 Hz, 1H, OCH₂), 4.34(d, J=10.7 Hz, 1H, OCH₂), 2.58-2.60 (m, 1H, Ar—CH), 2.37-2.39 (m, 1H,CHCO₂H), 1.87-2.11 (m, 2H, CH ₂CF₂), 0.66-1.69 (m, 29H, alkyl-H) Mass(ESI): 629 (M+1).

Example 41 Synthesis of10-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-decanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately,the same procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.01 (d, J=8.6 Hz, 2H, Ar—H), 6.89 (d, J=8.1Hz, 1H, Ar—H), 6.83 (d, J=8.5 Hz, 2H, Ar—H), 6.36-6.38 (m, 2H, Ar—H),4.45 (d, J=10.6 Hz, 1H, OCH₂), 4.34 (d, J=10.8 Hz, 1H, OCH₂), 2.56-2.58(m, 1H, Ar—CH), 2.46-2.48 (m, 1H, CHCO₂H), 2.08-2.23 (m, 2H, CH ₂CF₂),0.62-2.03 (m, 25H, alkyl-H). Mass (ESI): 701 (M+1).

Example 42 Synthesis of10-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-decanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately,the same procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR (270 MHz, CD₃OD): δ 7.02 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.3 Hz,1H, C5-CH), 6.77 (d, J=8.6 Hz, 2H), 6.30 (dd, J=8.3, 2.3 Hz, 1H, C6-CH),6.23 (d, J=2.3 Hz, 1H, C8-CH), 4.42 (d, J=11.0 Hz, 1H, C2-CH₂), 4.31 (d,J=11.0 Hz, 1H, C2-CH₂), 2.65-2.58 (m, 1H, C4-CH), 2.4-2.0 (m, 3H),1.7-0.9 (m, 22H), 0.9-0.7 (m, 2H), 0.68 (t, J=7.0 Hz, 3H).

Example 43 Synthesis of11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)-undecanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared separately, thesame procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.01 (d, J=8.3 Hz, 2H, Ar—H), 6.89 (d, J=8.2Hz, 1H, Ar—H), 6.82 (d, J=8.3 Hz, 2H, Ar—H), 6.36-6.38 (m, 2H, Ar—H),4.45 (d, J=10.6 Hz, 1H, OCH₂), 4.35 (d, J=10.6 Hz, 1H, OCH₂), 2.60-2.62(m, 1H, Ar—CH), 2.40-2.42 (m, 1H, CHCO₂H), 1.95-2.20 (m, 2H, CH ₂CF₂),0.67-1.80 (m, 29H, alkyl-H). Mass (ESI): 629 (M+1).

Example 44 Synthesis of11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)-undecanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared separately, the sameprocedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.04 (d, J=8.5 Hz, 2H, Ar—H), 6.92 (d, J=8.7Hz, 1H, Ar—H), 6.86 (d, J=8.7 Hz, 2H, Ar—H), 6.39-6.42 (m, 2H, Ar—H),4.48 (d, J=10.7 Hz, 1H, OCH₂), 4.37 (d, J=10.7 Hz, 1H, OCH₂), 2.62-2.64(m, 1H, Ar—CH), 2.35-2.45 (m, 1H, CHCO₂H), 1.92-2.11 (m, 2H, CH ₂CF₂),0.69-1.69 (m, 31H, alkyl-H). Mass (ESI): 643 (M+1).

Example 45 Synthesis of11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-undecanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared separately,the same procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.03 (d, J=8.7 Hz, 2H, Ar—H), 6.90 (d, J=8.2Hz, 1H, Ar—H), 6.85 (d, J=8.6 Hz, 2H, Ar—H), 6.37-6.41 (m, 2H, Ar—H),4.47 (d, J=10.5 Hz, 1H, OCH₂), 4.36 (d, J=10.9 Hz, 1H, OCH₂), 2.60-2.63(m, 1H, Ar—CH), 2.43-2.50 (m, 1H, CHCO₂H), 2.14-2.25 (m, 2H, CH ₂CF₂),0.65-2.02 (m, 27H, alkyl-H). Mass (ESI): 715 (M+1).

Example 46 Synthesis of11-[(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-undecanoicAcid

Starting with(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared separately,the same procedure as shown in Example 21 was repeated to give11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.00 (d, J=8.7 Hz, 2H, Ar—H), 6.90 (d, J=9.0Hz, 1H, Ar—H), 6.83 (d, J=8.6 Hz, 2H, Ar—H), 6.36-6.39 (m, 2H, Ar—H),4.45 (d, J=10.4 Hz, 1H, OCH₂), 4.35 (d, J=10.4 Hz, 1H, OCH₂), 2.59-2.62(m, 1H, Ar—CH), 2.40-2.43 (m, 1H, CHCO₂H), 2.02-2.14 (m, 2H, CH ₂CF₂),0.65-1.75 (m, 29H, alkyl-H). Mass (ESI): 729 (M+1).

Example 47 Synthesis of10-[(3RS,4RS)-3-Butyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicAcid

Starting with(3RS,4RS)-3-butyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chromanprepared as in Example 21 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately,the same procedure as shown in Example 21 was repeated to give10-[(3RS,4RS)-3-butyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.01 (d, J=8.7 Hz, 2H, Ar—H), 6.81-6.90 (m,3H, Ar—H), 6.35-6.37 (m, 2H, Ar—H), 4.45 (d, J=11.8 Hz, 1H, OCH₂), 4.34(d, J=10.7 Hz, 1H, OCH₂), 2.56-2.58 (m, 1H, Ar—CH), 2.41 (m, 1H,CHCO₂H), 1.95-2.17 (m, 2H, CH ₂CF₂), 0.68-1.76 (m, 29H, alkyl-H) Mass(ESI): 729 (M+1).

Example 48

Optical resolution of(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchromanprepared as in Example 21 was carried out using a chiral column(CHIRALPAK AD) to give optically active isomers.

Peaks 1 and 2 were detected at retention times of 7.3 and 8.0 minutes,respectively, under the following conditions:

Column used: CHIRALPAK AD (0.46 cm ID×25 cm L)

Mobile phase:hexane/isopropanol=100/1 (v/v)

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 254 nm

Example 49

Starting with the optically active isomer prepared in Example 48(Peak 1) and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoateprepared separately, the same procedure as shown in Example 21 wasrepeated to give10-[7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid having chiral carbons at positions 3 and 4.

This compound provided the same NMR data as shown in Example 42.

Example 50

Optical resolution of the10-[7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid having chiral carbons at positions 3 and 4 which was prepared inExample 49 was carried out using a chiral column (CHIRALPAK AD) to giveoptically active isomers, each having chiral carbons at positions 3 and4 and at α-position to the carboxyl group.

Each isomer provided the same NMR data as shown in Example 42.

Peaks 1 and 2 were detected at retention times of 6.9 and 8.3 minutes,respectively, under the following conditions:

Column used: CHIRALPAK AD (0.46 cm ID×25 cm L)

Mobile phase:hexane/isopropanol/acetic acid=80/20/0.1 (v/v/v)

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 280 nm

Example 51

Starting with the optically active isomer prepared in Example 48 (Peak2) and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate preparedseparately, the same procedure as shown in Example 21 was repeated togive10-[7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid having chiral carbons at positions 3 and 4.

This compound provided the same NMR data as shown in Example 42.

Example 52

Optical resolution of the10-[7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid having chiral carbons at positions 3 and 4 which was prepared inExample 51 was carried out using a chiral column (CHIRALCEL OJ) to giveoptically active isomers, each having chiral carbons at positions 3 and4 and at α-position to the carboxyl group.

Each isomer provided the same NMR data as shown in Example 42.

Peaks 1 and 2 were detected at retention times of 7.1 and 11.9 minutes,respectively, under the following conditions:

Column used: CHIRALCEL OJ (0.46 cm ID×25 cm L)

Mobile phase:hexane/ethanol/acetic acid=90/10/0.1 (v/v/v)

Flow rate: 1.0 ml/min

Column temperature: 40° C.

Detection wavelength: 280 nm

Test Example 1 Anti-estrogenic Activity (Oral Administration)

Test compounds were assayed for their oral anti-estrogenic activity inthe following manner. In this experiment, the compounds prepared inExamples mentioned above were used as test compounds. As controlcompounds, the following two were used: a compound described in Example7 of WO98/25916 and a compound corresponding to general formula (1) ofthe present invention, provided that R₁ was a methyl group, i.e.,10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid, which had been synthesized according to Reaction Schemes 1 to 7mentioned above.

To determine anti-estrogenic activity, mice (ICR, weight 30±2 g) whichhad been ovariectomized 2 weeks before were subcutaneously administeredwith 17β-estradiolbenzoate (Sigma) in an amount of 0.1 μg/mouse for 3days and the degree by which the test compound inhibited the increase inuterine weight was measured. In this experiment, each of the test andcontrol compounds was suspended in 5% arabic gum solution and orallyadministered for 3 days on a once-a-day basis. After 24 hours from thelast administration, the test animals were sacrificed and the uteri wereremoved and weighed. The results obtained are shown in Table 3 below.

TABLE 2 Anti-estrogenic activity in ovariectomized mice administeredwith 17β-estradiol (oral administration, 3 days) Test compound/dose(p.o., 3 days) Inhibition Compound mg/kg (%) Example 16 10 96 Example 1510 92 Example 14 10 81 Example 31 10 85 Example 20 10 91 Example 30 1089 Example 29 10 91 Example 22 10 83 Example 32 10 82 Example 34 10 90Example 35 10 93 Example 36 10 89 Example 38 10 84 Example 39 10 84Example 40 10 82 Example 41 10 89 Example 42 10 95 Example 43 10 85Example 44 10 84 Example 45 10 85 Example 46 10 94 Example 47 10 89Example 50, Peak 1 10 96 Example 50, Peak 2 10 95 Example 52, Peak 1 1093 Example 7 of WO98/25916 10 68.1 10-[(3Rs,4Rs)-7-hydroxy-3-(4- 10 75hydroxyphenyl)-3-methyl- thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid

The results shown in Table 3 above indicate that the compounds of thepresent invention show a superior inhibitory activity against theestradiol-induced increase in uterine weight, as compared to theanti-estrogenic compounds: the compound described in Example 7 ofWO98/25916 and10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid.

INDUSTRIAL APPLICABILITY

The compounds of the present invention are advantageous inpharmaceutical use because they have an excellent anti-estrogenicactivity as well as providing a sufficiently high activity even whenadministered orally.

What is claimed is:
 1. A compound having the following formula (1):

in which R₁ represents an ethyl group, a n-propyl group, an i-propylgroup or a butyl group; R₂ represents a hydrogen atom or a salt-formingmetal; R₃ represents a linear or branched C₁-C₇ halogenoalkyl group;each of R₄ and R₅ independently represents a hydrogen atom, anoptionally substituted linear or branched C₁-C₃ alkyl group, an acylgroup or a salt-forming metal; X represents an oxygen atom or a sulfuratom; m represents an integer of 2 to 14; and n represents an integer of2 to 7; or an enantiomer of the compound, or a hydrate or apharmaceutically acceptable salt of the compound or its enantiomer. 2.The compound according to claim 1, wherein each of R₄ and R₅ isindependently a hydrogen atom or a salt-forming metal, or an enantiomerof the compound, or a hydrate or a pharmaceutically acceptable salt ofthe compound or its enantiomer.
 3. The compound according to claim 1,wherein R₃ in formula (1) is a linear or branched C₁-C₇ fluoroalkylgroup, or an enantiomer of the compound, or a hydrate or apharmaceutically acceptable salt of the compound or its enantiomer. 4.The compound according to claim 1, wherein R₃ in formula (1) is a linearor branched C₁-C₅ perhalogenoalkyl group or a group of the followingformula (2):

in which each of R₆ and R₇ is a linear or branched C₁-C₃perhalogenoalkyl group, or an enantiomer of the compound, or a hydrateor a pharmaceutically acceptable salt of the compound or its enantiomer.5. The compound according to claim 3, wherein R₃ in formula (1) is alinear or branched C₁-C₅ perfluoroalkyl group or a group of thefollowing formula (2):

in which each of R₆ and R₇ is a linear or branched C₁-C₃ perfluoroalkylgroup, or an enantiomer of the compound, or a hydrate or apharmaceutically acceptable salt of the compound or its enantiomer. 6.The compound according to claim 1, wherein R₃ in formula (1) is a linearor branched C₂-C₄ perfluoroalkyl group, or an enantiomer of thecompound, or a hydrate or a pharmaceutically acceptable salt of thecompound or its enantiomer.
 7. The compound according to claim 1,wherein m in formula (1) is an integer of 6 to 10, or an enantiomer ofthe compound, or a hydrate or a pharmaceutically acceptable salt of thecompound or its enantiomer.
 8. The compound according to claim 1,wherein m in formula (1) is an integer of 8 to 10, or an enantiomer ofthe compound, or a hydrate or a pharmaceutically acceptable salt of thecompound or its enantiomer.
 9. The compound according to claim 1,wherein n in formula (1) is an integer of 2 to 6, or an enantiomer ofthe compound, or a hydrate or a pharmaceutically acceptable salt of thecompound or its enantiomer.
 10. The compound according to claim 1,wherein R₁ in formula (1) is an ethyl group or an n-propyl group, or anenantiomer of the compound, or a hydrate or a pharmaceuticallyacceptable salt of the compound or its enantiomer.
 11. The compoundaccording to claim 1, wherein in formula (1), R₁ is an ethyl group, ann-propyl group or a n-butyl group; R₂ is a hydrogen atom, an alkalimetal or an alkaline earth metal; R₃ is a perfluoroethyl group, aperfluoro-n-propyl group, a perfluoro-n-butyl group or a1,1,1,3,3,3-hexafluoroisopropyl group; X is an oxygen atom or a sulfuratom; m is an integer of 8 or 9; and n is an integer of 2 to 6; or anenantiomer of the compound, or a hydrate or a pharmaceuticallyacceptable salt of the compound or its enantiomer.
 12. The compoundaccording to claim 1, wherein in formula (1): a) R₁ is an ethyl group;R₂ is a hydrogen atom, R₃ is a perfluoroethyl group, X is a sulfur atom,m is 8, and n is 3; b) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃is a perfluoroethyl group, X is a sulfur atom, m is 8, and n is 4; c) R₁is an ethyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethyl group,X is a sulfur atom, m is 8, and n is 5; d) R₁ is an ethyl group, R₂ is ahydrogen atom, R₃ is a perfluorobutyl group, X is a sulfur atom, m is 8,and n is 2; e) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is aperfluoroethyl group, X is a sulfur atom, m is 9, and n is 3; f) R₁ isan ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutyl group, Xis a sulfur atom, m is 9, and n is 2; g) R₁ is an n-propyl group, R₂ isa hydrogen atom, R₃ is a perfluoroethyl group, X is a sulfur atom, m is8, and n is 3; h) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is aperfluoroethyl group, X is an oxygen atom, m is 9, and n is 5; i) R₁ isan ethyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutyl group, Xis an oxygen atom, m is 9, and n is 2; j) R₁ is an ethyl group, R₂ is ahydrogen atom, R₃ is a perfluorobutyl group, X is an oxygen atom, m is8, and n is 3; k) R₁ is an ethyl group, R₂ is a hydrogen atom, R₃ is aperfluorobutyl group, X is an oxygen atom, m is 9, and n is 3; l) R₁ isan n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethyl group,X is a sulfur atom, m is 8, and n is 4; m) R₁ is an n-propyl group, R₂is a hydrogen atom, R₃ is a perfluorobutyl group, X is a sulfur atom, mis 8, and n is 2; n) R₁ is an n-propyl group, R₂ is a hydrogen atom, R₃is a perfluoroethyl group, X is a sulfur atom, m is 9, and n is 3; o) R₁is an n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is a sulfur atom, m is 9, and n is 2; p) R₁ is an n-propylgroup, R₂ is a hydrogen atom, R₃ is a perfluoroethyl group, X is anoxygen atom, m is 8, and n is 4; q) R₁ is an n-propyl group, R₂ is ahydrogen atom, R₃ is a perfluorobutyl group, X is an oxygen atom, m is8, and n is 2; s) R₁ is an n-propyl group, R₂ is a hydrogen atom, R₃ isa perfluorobutyl group, X is an oxygen atom, m is 8, and n is 3; t) R₁is an n-propyl group, R₂ is a hydrogen atom, R₃ is a perfluoroethylgroup, X is an oxygen atom, m is 9, and n is 3; u) R₁ is an n-propylgroup, R₂ is a hydrogen atom, R₃ is a perfluoroethyl group, X is anoxygen atom, m is 9, and n is 4; v) R₁ is an n-propyl group, R₂ is ahydrogen atom, R₃ is a perfluorobutyl group, X is an oxygen atom, m is9, and n is 2; w) R₁ is an n-propyl group, R₂ is a hydrogen atom, R₃ isa perfluorobutyl group, X is an oxygen atom, m is 9, and n is 3; x) R₁is an n-butyl group, R₂ is a hydrogen atom, R₃ is a perfluorobutylgroup, X is an oxygen atom, m is 8, and n is 3; or y) R₁ is an n-propylgroup, R₂ is a hydrogen atom, R₃ is a perfluorobutyl group, X is anoxygen atom, m is 8, and n is 3; or an enantiomer of the compound, or ahydrate or a pharmaceutically acceptable salt of the compound or itsenantiomer.
 13. The compound according to claim 1, wherein in formula(1), the configuration of 3- and 4-position carbons in the parentscaffold (chroman or thiochroman ring) is (3RS,4RS), (3R,4R) or (3S,4S),or an enantiomer of the compound, or a hydrate or a pharmaceuticallyacceptable salt of the compound or its enantiomer.
 14. The compoundaccording to claim 1, wherein in formula (1), the carbon to which acarboxylic acid or its metal salt is bonded has R- or S-configuration,wherein said carbon is the carbon on the side chain which is bonded to4-position of the parent scaffold (chroman or thiochroman ring), or amixture thereof, or an enantiomer of the compound, or a hydrate or apharmaceutically acceptable salt of the compound or its enantiomer. 15.The compound according to claim 1, which is selected from the groupconsisting of:10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid;10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid;10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-decanoicacid;11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-undecanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid;11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoicacid;11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-undecanoicacid;10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-decanoicacid;11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)-chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-undecanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-decanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,5,-pentafluoropentyl)-undecanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-undecanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid;10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-decanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-undecanoicacid;11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-undecanoicacid;10-[(3RS,4RS)-3-butyl-7-hydroxy-3-(4-hydroxyphenyl)-chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-decanoicacid; and10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-decanoicacid; or an enantiomer of the compound, or a hydrate or apharmaceutically acceptable salt of the compound or its enantiomer. 16.A compound represented by Peak 1 or 2 shown in the following formula:

wherein said Peaks 1 and 2 are detected at retention times of 6.9 and8.3 minutes, respectively, when optically resolved and measured underthe following conditions: Column used: CHIRALPAK AD (0.46 cm ID×25 cm L)Mobile phase:hexane/isopropanol/acetic acid=80/20/0.1 (v/v/v) Flow rate:1.0 ml/min Column temperature: 40° C. Detection wavelength: 280 nm. 17.A compound represented by Peak 1 or 2 shown in the following formula:

wherein said Peaks 1 and 2 are detected at retention times of 7.1 and11.9 minutes, respectively, when optically resolved and measured underthe following conditions: Column used: CHIRALCEL OJ (0.46 cm ID×25 cm L)Mobile phase:hexane/ethanol/acetic acid=90/10/0.1 (v/v/v) Flow rate: 1.0ml/min Column temperature: 40° C. Detection wavelength: 280 nm.
 18. Apharmaceutical composition comprising as an active ingredient, at leastone compound according to any one of claims 1 to 15 or enantiomerthereof, or at least one hydrate or pharmaceutically acceptable salt ofthe compound or its enantiomer.
 19. An anti-estrogenic pharmaceuticalcomposition comprising as an active ingredient, at least one compoundaccording to any one of claims 1 to 17 or enantiomer thereof, or atleast one hydrate or pharmaceutically acceptable salt of the compound orits enantiomer.
 20. A therapeutic agent for breast cancer comprising asan active ingredient, at least one compound according to any one ofclaims 1 to 17 or enantiomer thereof, or at least one hydrate orpharmaceutically acceptable salt of the compound or its enantiomer.